Azabicyclo[2.2.1]Heptane Compounds as Alpha-7 Nicotinic Acetylcholine Receptor Ligands

ABSTRACT

The disclosure provides compounds of formula I, including Ia, Ib, Ic, or Id, including their salts, as well as compositions and methods of using the compounds. The compounds are ligands for the nicotinic α7 receptor and may be useful for the treatment of various disorders of the central nervous system, especially affective and neurodegenerative disorders.

CROSS REFERENCE TO RELATED APPLICATIONS

This patent application claims the benefit of U.S. provisional patentapplication No. 61/255,782 filed Oct. 28, 2009.

BACKGROUND OF THE INVENTION

The disclosure generally relates to compounds of formula I, includingIa, Ib, Ic, or Id, including their salts, as well as compositions andmethods of using the compounds. The compounds are ligands, agonists andpartial agonists for the nicotinic α7 receptor and may be useful for thetreatment of various disorders of the central nervous system, especiallyaffective and neurodegenerative disorders.

Schizophrenia is a serious mental disorder, affecting approximately 1%of the population. Its progressive course results in major impairment ofmental and social functioning and often leads to the development ofother pathologies. Susceptibility often runs in families, with bothgenetic and environmental factors thought to be important. The directand indirect costs of the disease are estimated in the tens of billiondollars annually in the U.S. alone.

Patients with schizophrenia have an elevated risk of suicide(approximately a 10% lifetime risk). They have a 2.5 fold increase inall-cause mortality, resulting in a 20% lowered life expectancy. Theonset of illness can result in cascade of unhealthy lifestyle factorsand behaviors that elevate the risk of various conditions andconsequently the risk of death.

The onset of schizophrenia is most often in late adolescence or earlyadulthood, and episodes recur throughout life. The disease ischaracterized by the expression of three distinct symptom domains:positive, negative and cognitive. Psychotic or positive symptoms includedelusions, hallucinations, thought disorder and paranoia. Negativesymptoms include negative affect, social withdrawal, and anhedonia.Cognitive dysfunction includes deficits in attention, working memory andexecutive function. The pathophysiology of schizophrenia is not wellunderstood, however, most experts believe it is a multi-factorialdisorder in which biological, genetic and environmental factors play arole. Most current therapies target the dopaminergic system and haveresulted in the suggestion that an excess of dopaminergicneurotransmission underlies at least some aspects of schizophrenia. Thistheory received further support from findings that drugs which increasethe levels of dopamine cause psychoses similar to the positive symptomsof the disease. Also, post mortem analysis of brains from schizophrenicpatients indicate increased numbers of D2 dopamine receptors. Althoughnewer antipsychotic agents, known as atypical antipsychotics, which areactive at several additional neurotransmitter receptors, have beenintroduced in the past decade, these agents still share efficacy againstthe D2 dopamine receptor. All currently-used agents also have majorlimitations. Although positive symptoms are generally reduced in amajority of patients, these drugs do little to relieve the negativesymptoms and cognitive deficits that are common and often mostdebilitating. In addition, antipsychotic agents have a number ofunwanted and limiting side effects.

Nicotine is among the few agents which have a positive effect oncognitive function. Many schizophrenics smoke; the rate in patients is2-4 times that of the general population, and up to 90% inschizophrenics who have been institutionalized do smoke. This smokinghabit has been characterized as a form of self-medication.

Nicotinic acetylcholine receptors (nAChR's) are pentameric ligand-gatedion channels which are widely expressed through the central andperipheral nervous system. These channels are fast-desensitizing calciumchannels which, when open, increase the intracellular concentration ofthe Ca⁺⁺ ion. Although there are 12 individual receptors, the mostabundant nicotinic receptors in the brain are α4β2 and α7. The α4β2complex has been identified as the “high affinity” nicotine site. Thehomo-pentameric α7 receptor selectively binds the natural product,α-bungarotoxin, which has allowed its relatively facile localization andmeasurement. The α7 receptor is primarily expressed in the cortex,hippocampus and subcortical limbic regions and commonly occurspre-synaptically. The localization of α7 nAChRs in areas involved withlearning and memory has led to studies using both knockout mice andpharmacological manipulation. It is involved in sensory gating, memory,and neuronal plasticity. Alpha7 agonists have been shown to increase therelease of neurotransmitters in rodents, including dopamine, serotonin,glutamate and GABA. Compounds which selectively bind to the α7 receptor,such as α7 agonists and partial agonists, have been shown to improvelearning and memory functions in normal and aged animals, reversescopolamine-induced memory deficits, reverse deficits in cognitioninduced by NMDA antagonists, reverse pharmacologically-induced gatingdeficits, e.g. amphetamine induced gating disruption, and to possesssome anxiolytic properties. The α7 agonists of the present invention areexpected to be useful in the treatment of schizophrenia and cognitivedisorders associated with schizophrenia.

Alzheimer's disease is a progressive neurodegenerative disorder,resulting in the general loss of cognitive functions. The incidenceincreases with age, to the degree that 25-50% of all individuals over 85are estimated to suffer from some degree of dementia. A diagnosis ofAlzheimer's implies that the remaining life expectancy is reduced byhalf, compared to normal adults.

Clinical signs of Alzheimer's disease are progressive cognitivedeterioration, decreased ability to perform the activities of dailyliving and neuropsychiatric symptoms or behavioral changes. In theadvanced stages of the disease, deterioration of musculature andmobility may lead to inability to feed oneself, and eventually to thepatient becoming bedridden. Language becomes severely disorganized, andthen is lost altogether. Patients are not able to perform even simpletasks independently and require constant supervision. The cost ofinstitutional care makes up nearly 70% of the cost of the disease.Therefore, therapies which increase cognitive function and delayinstitutionalization are greatly needed.

Alzheimer's disease has been shown in several studies to be accompaniedby a reduction in nicotinic receptors in the cortex and hippocampus.Nicotine injections or nicotine skin patches have been reported tosignificantly improve attention, memory and learning in Alzheimer'sdisease patients. While there is a progressive loss of nicotinicreceptors during the course of Alzheimer's disease, the α7 neurons arerelatively spared, compared to the more abundant α4 receptors. Recently,the administration of selective nicotinic α7 agonists has been shown toincrease cognitive functioning in Alzheimer's patients when dosed aslong as 8 weeks. This clinical data is consistent with pre-clinical datashowing α7 agonists and partial agonists improve learning and memoryfunctions in normal and aged animals and reverse scopolamine-inducedmemory deficits. Thus, the compounds of the present invention may beuseful in the treatment and prevention of Alzheimer's disease. Theamyloid peptide Aβ42 has been shown to bind to the α7 nicotinic receptor(Wang et al., J. Biol. Chem., 2000, 275:5626-5632; J. Neurochem. 2000,75:1155-1161). This association may facilitate the aggregation of Aβ42,believed to be important in the toxic effects of Aβ42, and may alsocause disregulation of signaling through α7 nicotinic receptors.Deletion of the a7 receptor gene improves cognitive deficits andsynaptic pathology in a mouse model of Alzheimer's disease(Dziewczapolski et al., J. Neuroscience, 2009, pp 8805-8815). Thecompounds of the present invention may disrupt the interaction of Aβ42and α7 receptors. Treatment with α7 agonists and partial agonists mayrepresent an approach for disease modification in Alzheimer's disease.Alpha7 receptors may also mediate inflammatory processes inneurodegenerative conditions, such as Alzheimer's disease(Conejero-Goldberg et al., Neurosci. and Biobehay. Rev., 2008, 32, pp693-706). The α7 agonists and partial agonists of the present inventionmay be useful in reducing inflammation in neurodegenerative diseases anddisorders, such as Alzheimer's disease.

The α7 receptor has also been shown to be involved in the reduction ofinflammation via the vagus nerve. In addition, the α7 receptor isexpressed in synoviocytes from RA and OA patients, and α7 agonists havebeen shown to inhibit the proinflammatory cascade that occurs in therheumatoid joint (Waldberger et al., Arthritis and Rheumatism, Vol 58,pp 3439-3449). Thus, the compounds of the present invention may beuseful in the treatment of inflammatory conditions, such as rheumatoidarthritis and osteoarthritis.

Nicotinic receptors containing the α7 subunit are present on mucosalmast cells known to be involved in gastrointestinal hypersensitivity(Kageyama-Yahara et al., Biochem and Biophys. Research Commun., 2008, v.377, pp 321-325). The α7 agonist GTS-21 inhibits the antigen-induceddegranulation of mucosal mast cells, suggesting that α7 agonists may beuseful in the treatment of hypersensitive bowel conditions, such asulcerative colitis.

In a recent report (Marrero et al., JPET Fast Forward, Sep. 28, 2009,DOI: 10.1124/jpet.109.154633), an α7 agonist was shown to decreaseweight gain and food intake and reduce the elevated plasma levels oftriglycerides, glucose, glycated hemoglobin and TNFa in a mouse model oftype II diabetes (db/db mice which are deficit in leptin receptors). Theα7 agonists and partial agonists of the present invention may be usefulin the treatment of diabetes.

The following references provide general reviews of the nicotinicreceptor system and α7 receptors and ligands: Picciotto and Zoli, J.Neurobio. (2002) 53:641-655; Brening, et al, Ann. Reports in Med. Chem.(2005) 40:3-16; Dani and Bertrand, Ann. Rev. Pharm. Tox. (2007)47:699-729; Olincy and Stevens, Biochem. Pharmacol. (2007) 74:1192-1201;Broad, et al, Drugs Future (2007) 32 (2):161-70; de Jonge and Ulloa,Brit. J. Pharmacol. (2007) 151:915-929; Romanelli, et al, Chem Med Chem(2007) 2(6):746-767; Lightfoot et al., Progress in Medicinal Chemistry(2008), v 46, pp 131-171; Concotta et al., Current Opinion inInvestigational Drugs (2008), v 9, pp 47-56; Leiser et al., Pharmacol.and Therapeutics (2009), doi:10:1016/j.pharmthera.2009.03.009).

Ligands for the nicotinic α7 receptor have been disclosed in thereferences above, and also in US patent application publication U.S.20090270405, U.S. 2007004715, WO 2008/000469, WO 2003/092580, WO2004/000,469, EP 337,547, EP 452,101, and C. J. Swain, et al., J. Med.Chem., (1992) 35:1019-1031.

The invention provides technical advantages, for example, the compoundsare novel and are ligands for the nicotinic α7 receptor and may beuseful for the treatment of various disorders of the central nervoussystem, especially affective and neurodegenerative disorders.Additionally, the compounds provide advantages for pharmaceutical uses,for example, with regard to one or more of their mechanism of action,binding, inhibition efficacy, target selectivity, solubility, safetyprofiles, or bioavailability.

DESCRIPTION OF THE INVENTION

The invention encompasses compounds formula I, including Ia, Ib, Ic, orId, including pharmaceutically acceptable salts, and compositions andmethods of treatment using these compounds. The compounds may be usefulfor the treatment of various disorders of the central nervous system:

One aspect of the invention is a compound of formula I, or astereoisomer thereof,

wherein:

-   R¹ is selected from the group consisting of isoxazolyl, pyrazolyl,    oxazolyl, thiazolyl, imidazolyl, oxadiazolyl, thiadiazolyl,    triazolyl, pyridinyl, pyrazinyl, pyridazinyl, pyrimidinyl,    triazinyl, quinolinyl, isoquinolinyl, tetrahydroisoquinolinyl,    quinoxalinyl, quinazolinyl, naphthyridinyl, indazolyl, indolyl,    2-indolonyl, benzisoxazolyl, benzoisothiazolyl, benzoxazolyl,    benzothiazolyl, benzimidazolyl, furopyridinyl, thienopyridinyl,    thienopyrimidinyl, isothiazolopyridinyl, thiazolopyridinyl,    thiazolopyridinonyl, thiazolopyrazinyl, thiazolopyrimidinyl,    triazolopyridinyl, triazolopyrazinyl, pyrrolotriazinyl,    5,6-dihydrobenzo[h]quinazolinyl, 5H-chromeno[4,3-d]pyrimidinyl,    6,7-dihydro-5H-cyclopenta[d]pyrimidinyl,    5,6,7,8-tetrahydroquinazolinyl, 7,8-dihydroquinazolin-5(6H)-onyl,    and tetrahydrobenzothiazolyl, and is substituted with 0-3    substituents independently selected from the group consisting of    C₁₋₄alkyl, C₃₋₇cycloalkyl, C₁₋₄haloalkyl, C₁₋₄alkoxy,    C₁₋₄haloalkoxy, C₃₋₇cycloalkoxy, C₁₋₄alkylthio, phenoxy, benzyloxy,    halo, hydroxy, cyano, nitro, C₁₋₄alkylsulfonyl, NR²R³,    pyrrolidinonyl, methylenedioxy, furyl, thienyl, pyrazolyl,    imidazolyl, thiazolyl, triazolyl, pyrazinyl, pyrimidinyl, naphthyl,    C₁₋₄alkylamido, CONR²R³, pyridyl, phenyl, and benzyl, and where    imidazolyl, pyridyl, phenyl and benzyl are substituted with 0-2    substituents independently selected from the group consisting of    halo, C₁₋₄alkyl, C₁₋₄alkoxy, C₁₋₄haloalkyl, C₁₋₄haloalkoxy, and    NR²R³;-   R² is hydrogen, C₁₋₄alkyl, C₁₋₄hydroxyalkyl, or C₁₋₄aminoalkyl;-   R³ is hydrogen, C₁₋₄alkyl, C₁₋₄hydroxyalkyl, or C₁₋₄aminoalkyl;-   or R₂ and R₃ taken together with the nitrogen atom to which they are    attached is axetidinyl, pyrrolidinyl, piperidinyl, piperazinyl,    N—(C₁₋₄alkyl)piperazinyl, morpholinyl, or homopiperidinyl;-   or a pharmaceutically acceptable salt thereof.

Another aspect of the invention is the stereoisomer of formula Iaccording to formula Ia.

Another aspect of the invention is the stereoisomer of formula Iaccording to formula Ib.

Another aspect of the invention is the stereoisomer of formula Iaccording to formula Ic.

Another aspect of the invention is the stereoisomer of formula Iaccording to formula Id.

Another aspect of the invention is a compound of formula I, includingIa, Ib, Ic, or Id where R¹ is selected from the group consisting ofdimethylisoxazolyl, (methyl)(phenyl)isoxazolyl, methylpyrazolyl,dimethylpyrazolyl, thienylpyrazolyl, methoxyphenylpyrazolyl, thiazolyl,bromothiazolyl, cyanothiazolyl, methylthiazolyl, dimethylthiazolyl,(methyl)(phenyl)thiazolyl, isopropylthiazolyl, butylthiazolyl,benzylthiazolyl, methoxyphenylmethylthiazolyl, phenylthiazolyl,chlorophenylthiazolyl, methoxyphenylthiazolyl,(methoxyphenyl)(methyl)thiazolyl, pyridinylthiazolyl,(phenyl)(methyl)imidazolyl, methyloxadiazolyl, ethyloxadiazolyl,methylthiadiazolyl, fluorophenylthiadiazolyl, furylthiadiazolyl,(dimethylcarboxamido)(methyl)thiazolyl, (pyrrolidinylCO)thiazolyl,phenyltriazolyl, pyridinyl, bromopyridinyl, chloropyridinyl,(chloro)(fluoro)pyridinyl, (chloro)(methyl)pyridinyl, dichloropyridinyl,fluoropyridinyl, cyanopyridinyl, (cyano)(methyl)pyridinyl,(cyano)(dimethyl)pyridinyl, methoxypyridinyl,(methylpyrrolidinyl)pyridinyl, phenylpyridinyl,methoxypyridinylpyridinyl, pyridazinyl, bromopyridazinyl,chloropyridazinyl, methylpyridazinyl, methoxypyridazinyl,methylthiopyridazinyl, pyrrolidinylpyridazinyl,pyrrolidinonylpyridazinyl, phenylpyridazinyl, pyridinylpyridazinyl,methoxypyridinylpyridazinyl, pyrimidinyl, (bromo)(isopropyl)pyrimidinyl,(bromo)(dimethyl)pyrimidinyl, (bromo)(cyclopropyl)pyrimidinyl,(bromo)(methoxy)pyrimidinyl, (bromo)(phenyl)pyrimidinyl,(bromo)(pyridinyl)pyrimidinyl, chloropyrimidinyl,(chloro)(dimethyl)pyrimidinyl, (methyl)(methoxy)pyrimidinyl,methylpyrimidinyl, ethylpyrimidinyl, (methyl)(phenyl)pyrimidinyl,dimethylpyrimidinyl, butylpyrimidinyl, isopropylpyrimidinyl,cyclopropylpyrimidinyl, methoxypyrimidinyl, dimethoxypyrimidinyl,isopropoxypyrimidinyl, cyclopentoxypyrimidinyl,difluoromethoxypyrimidinyl, trifluoroethoxypyrimidinyl,phenoxypyrimidinyl, methylthiopyrimidinyl, phenylpyrimidinyl,chlorophenylpyrimidinyl, methylphenylpyrimidinyl,methoxyphenylpyrimidinyl, (phenyl)(triazolyl)pyrimidinyl,pyridinylpyrimidinyl, methoxypyridinylpyrimidinyl,methoxypyrimidinylpyrimidinyl, naphthylpyrimidinyl, pyrazinyl,bromopyrazinyl, (bromo)(methoxy)pyrazinyl, chloropyrazinyl,methylpyrazinyl, dimethylpyrazinyl, butylpyrazinyl, cyanopyrazinyl,methoxypyrazinyl, isopropoxypyrazinyl, trifluoromethylpyrazinyl, andphenylpyrazinyl, and dimethyltriazinyl; or a pharmaceutically acceptablesalt thereof.

Another aspect of the invention is a compound of formula I, includingIa, Ib, Ic, or Id where R¹ is selected from the group consisting ofdimethylpyridinoisoxazolyl, benzoxazolyl, chlorobenzoxazolyl,fluorophenylbenzoxazolyl, ethylphenylbenzoxazolyl,dimethylaminophenylbenzoxazolyl, pyridinylbenzoxazolyl, benzothiazolyl,acetamidobenzothiazolyl, bromobenzothiazolyl, chlorobenzothiazolyl,(chloro)(methyl)benzothiazolyl, (chloro)(methoxy)benzothiazolyl,fluorobenzothiazolyl, difluorobenzothiazolyl, cyanobenzothiazolyl,methylbenzothiazolyl, dimethylbenzothiazolyl,(methyl)(methoxy)benzothiazolyl, ethylbenzothiazolyl,trifluoromethylbenzothiazolyl, hydroxybenzothiazolyl,methoxybenzothiazolyl, ethoxybenzothiazolyl, isopropoxybenzothiazolyl,trifluoromethoxybenzothiazolyl, difluoromethoxybenzothiazolyl,dimethoxybenzothiazolyl, morpholinylbenzothiazolyl,(pyrrolidinylCO)benzothiazolyl, methylsulfonylbenzothiazolyl,chlorothiazolopyridinyl, dimethylthiazolopyridinyl,benzyloxythiazolopyridinyl, difluoromethoxythiazolopyridinyl,benzotriazolyl, indolonyl, indazolyl, bromoindazolyl, chloroindazolyl,fluoroindazolyl, (methyl)(methoxy)indazolyl, methoxyindazolyl,trifluoromethylindazolyl, trifluoromethoxyindazolyl,difluoromethoxyindazolyl, benzimidazolyl, fluorobenzimidazolyl,methylbenzimidazolyl, (methyl)(methoxy)benzimidazolyl,methoxybenzimidazolyl, tetrahydrobenzothiazolyl, furopyridinyl,dimethylfuropyrimidinyl, thienopyrimidinyl, isopropylthienopyrimidinyl,dimethylthienopyrimidinyl, chlorotriazolopyridinyl,methyltriazolopyridinyl, trifluoromethyltriazolopyridinyl,methoxytriazolopyridinyl, triazolopyrazinyl, bromopyrrolotriazinyl,dimethylaminothiazolopyrimidinyl, thiazolopyazinyl,bromothiazolopyazinyl, methoxythiazolopyazinyl,methylthiothiazolopyazinyl, methoxythiazolopyrimidinyl,(methyl)(methoxy)thiazolopyrimidinyl, quinolinyl, bromoquinolinyl,fluoroquinolinyl, methylquinolinyl, (methyl)(methoxy)quinolinyl,isoquinolinyl, bromoisoquinolinyl, dichloroisoquinolinyl,methylisoquinolinyl, dimethylisoquinolinyl, quinoxalinyl,chloroquinoxalinyl, methylquinoxalinyl, methoxyquinoxalinyl,quinazolinyl, bromoquinazolinyl, naphthyridinyl,5,6-dihydrobenzo[h]quinazolinyl, 5H-chromeno[4,3-d]pyrimidinyl,6,7-dihydro-5H-cyclopenta[d]pyrimidinyl, 5,6,7,8-tetrahydroquinazolinyl,and 7,8-dihydroquinazolin-5(6H)-onyl; or a pharmaceutically acceptablesalt thereof.

Another aspect of the invention is a compound of formula I, includingIa, Ib, Ic, or Id where R¹ is selected from the group consisting ofdichloropyridinyl, methoxypyridinyl, methoxypyrimidinyl,phenylpyrimidinyl, (methylphenyl)pyrimidinyl, pyridinylpyrimidinyl,chloropyrazinyl, benzothiazolyl, methoxybenzothiazolyl,thiazolopyridinyl, chlorothiazolopyridinyl, fluorothiazolopyridinyl,methoxythiazolopyridinyl, and isoquinoinyl, or a pharmaceuticallyacceptable salt thereof.

Another aspect of the invention is a compound of formula I, includingIa, Ib, Ic, or Id where R¹ is selected from the group consisting ofimidazolylpyrimidinyl, (chloroimidazolyl)pyrimidinyl,(triazolyl)pyrimidinyl, (methylimidazolyl)pyrimidinyl,(methoxy)(pyrrolidinyl)pyrimidinyl, benzo[e][1,2,4]triazinyl,chlorobenzoxazolyl, pyrrolo[1,2-f][1,2,4]triazinyl,thieno[3,2-d]pyrimidinyl, methylthieno[3,2-d]pyrimidinyl, andmethylbenzoxazolyl; or a pharmaceutically acceptable salt thereof.

Another aspect of the invention is a compound or formula I, includingIa, Ib, Ic, or Id where R¹ is selected from the group consisting ofthiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl,benzothiazolyl, thiazolopyridinyl, indazolyl, benzimidazolyl,isoquinolinyl, and quinazolinyl, and is substituted with 0-3substituents independently selected from the group consisting ofC₁₋₄alkyl, C₃₋₇cycloalkyl, C₁₋₄haloalkyl, C₁₋₄alkoxy, C₁₋₄haloalkoxy,C₃₋₇cycloalkoxy, C₁₋₄alkylthio, phenoxy, benzyloxy, halo, hydroxy,cyano, C₁₋₄alkylsulfonyl, NR²R³, pyrrolidinonyl, methylenedioxy, furyl,thienyl, triazolyl, pyrimidinyl, naphthyl, C₁₋₄alkylamido, CONR²R³,pyridyl, phenyl, and benzyl, and where pyridyl, phenyl and benzyl aresubstituted with 0-2 substituents independently selected from the groupconsisting of halo, C₁₋₄alkyl, C₁₋₄alkoxy, C₁₋₄haloalkyl,C₁₋₄haloalkoxy, and NR²R³; or a pharmaceutically acceptable saltthereof.

Another aspect of the invention is a compound or formula I, includingIa, Ib, Ic, or Id where R¹ is selected from the group consisting ofpyridinyl, pyrimidinyl, pyrazinyl, thiazolopyridinyl, and isoquinolinyl,and is substituted with 0-3 substituents independently selected from thegroup consisting of C₁₋₄alkyl, C₃₋₇cycloalkyl, C₁₋₄haloalkyl,C₁₋₄alkoxy, C₁₋₄haloalkoxy, C₃₋₇cycloalkoxy, C₁₋₄alkylthio, phenoxy,benzyloxy, halo, hydroxy, cyano, C₁₋₄alkylsulfonyl, NR²R³,pyrrolidinonyl, methylenedioxy, furyl, thienyl, triazolyl, pyrimidinyl,naphthyl, C₁₋₄alkylamido, CONR²R³, pyridyl, phenyl, and benzyl, andwhere pyridyl, phenyl and benzyl are substituted with 0-2 substituentsindependently selected from the group consisting of halo, C₁₋₄alkyl,C₁₋₄alkoxy, C₁₋₄haloalkyl, C₁₋₄haloalkoxy, and NR²R³; or apharmaceutically acceptable salt thereof.

Another aspect of the invention is a compound or formula I, includingIa, Ib, Ic, or Id where R¹ is selected from the group consisting ofpyridinyl and isoquinolinyl, and is substituted with 0-3 substituentsindependently selected from the group consisting of C₁₋₄alkyl,C₃₋₇cycloalkyl, C₁₋₄haloalkyl, C₁₋₄alkoxy, C₁₋₄haloalkoxy,C₃₋₇cycloalkoxy, C₁₋₄alkylthio, phenoxy, benzyloxy, halo, hydroxy,cyano, C₁₋₄alkylsulfonyl, NR²R³, pyrrolidinonyl, methylenedioxy, furyl,thienyl, triazolyl, pyrimidinyl, naphthyl, C₁₋₄alkylamido, CONR²R³,pyridyl, phenyl, and benzyl, and where pyridyl, phenyl and benzyl aresubstituted with 0-2 substituents independently selected from the groupconsisting of halo, C₁₋₄alkyl, C₁₋₄alkoxy, C₁₋₄haloalkyl,C₁₋₄haloalkoxy, and NR²R³; or a pharmaceutically acceptable saltthereof.

Another aspect of the invention is a compound or formula I, includingIa, Ib, Ic, or Id where R¹ is selected from the group consisting ofpyridinyl, pyrimidinyl, pyrazinyl, thiazolopyridinyl, isoquinolinyl, andbenzoxazolyl, and is substituted with 0-3 substituents independentlyselected from the group consisting of C₁₋₄alkyl, C₃₋₇cycloalkyl,C₁₋₄haloalkyl, C₁₋₄alkoxy, C₁₋₄haloalkoxy, C₃₋₇cycloalkoxy, halo,hydroxy, cyano, NR²R³, pyrrolidinonyl, methylenedioxy, furyl, thienyl,triazolyl, imidazolyl, thiazolyl, oxazolyl, pyrimidinyl, naphthyl,C₁₋₄alkylamido, CONR²R³, pyridyl, and phenyl, and where pyridyl, phenyl,thiazolyl and imidazolyl are substituted with 0-2 substituentsindependently selected from the group consisting of halo, C₁₋₄alkyl,C₁₋₄alkoxy, C₁₋₄haloalkyl, C₁₋₄haloalkoxy, and NR²R³; or apharmaceutically acceptable salt thereof.

Another aspect of the invention is a compound selected from the groupconsisting of

-   (3R*,4S*)-N-(6-methoxybenzo[d]thiazol-2-yl)-4′H-1-azaspiro[bicyclo[2.2.1]heptane-3,5′-oxazol]-2′-amine,    (3R*,4R*)-N-(6-methoxybenzo[d]thiazol-2-yl)-4′H-1-azaspiro[bicyclo[2.2.1]heptane-3,5′-oxazol]-2′-amine,    (3R*,4R*)-N-(5-chlorothiazolo[5,4-b]pyridin-2-yl)-4′H-1-azaspiro[bicyclo[2.2.1]heptane-3,5′-oxazol]-2′-amine,    (3R*,4R*)-N-(5-fluorothiazolo[5,4-b]pyridin-2-yl)-4′H-1-azaspiro[bicyclo[2.2.1]heptane-3,5′-oxazol]-2′-amine,    (3R*,4R*)-N-(5-methoxythiazolo[5,4-b]pyridin-2-yl)-4′H-1-azaspiro[bicyclo[2.2.1]heptane-3,5′-oxazol]-2′-amine,    (3R*,4R*)-N-(3,5-dichloropyridin-2-yl)-4′H-1-azaspiro[bicyclo[2.2.1]heptane-3,5′-oxazol]-2′-amine,    (3R*,4R*)-N-(isoquinolin-3-yl)-4′H-1-azaspiro[bicyclo[2.2.1]heptane-3,5′-oxazol]-2′-amine,    (3R,4R)—N-(isoquinolin-3-yl)-4′H-1-azaspiro[bicyclo[2.2.1]heptane-3,5′-oxazol]-2′-amine,    (3S,4S)—N-(isoquinolin-3-yl)-4′H-1-azaspiro[bicyclo[2.2.1]heptane-3,5′-oxazol]-2′-amine,    (3R*,4R*)-N-(thiazolo[5,4-b]pyridin-2-yl)-4′H-1-azaspiro[bicyclo[2.2.1]heptane-3,5′-oxazol]-2′-amine    amine,    (3S,4S)—N-(thiazolo[5,4-b]pyridin-2-yl)-4′H-1-azaspiro[bicyclo[2.2.1]heptane-3,5′-oxazol]-2′-amine,    (3R,4R)—N-(thiazolo[5,4-b]pyridin-2-yl)-4′H-1-azaspiro[bicyclo[2.2.1]heptane-3,5′-oxazol]-2′-amine,    (3R*,4R*)-N-(5-m-tolylpyrimidin-2-yl)-4′H-1-azaspiro[bicyclo[2.2.1]heptane-3,5′-oxazol]-2′-amine,    (3R*,4R*)-N-(5-methoxypyridin-2-yl)-4′H-1-azaspiro[bicyclo[2.2.1]heptane-3,5′-oxazol]-2′-amine,    (3R,4R)—N-(6-(pyridin-3-yl)pyrimidin-4-yl)-4′H-1-azaspiro[bicyclo[2.2.1]heptane-3,5′-oxazol]-2′-amine,    (3R,4R)—N-(benzo[d]thiazol-2-yl)-4′H-1-azaspiro[bicyclo[2.2.1]heptane-3,5′-oxazol]-2′-amine,    (3R,4R)—N-(6-methoxypyrimidin-4-yl)-4′H-1-azaspiro[bicyclo[2.2.1]heptane-3,5′-oxazol]-2′-amine,    (3R,4R)—N-(5-chloropyrazin-2-yl)-4′H-1-azaspiro[bicyclo[2.2.1]heptane-3,5′-oxazol]-2′-amine,    (3R,4R)—N-(4-phenylpyrimidin-2-yl)-4′H-1-azaspiro[bicyclo[2.2.1]heptane-3,5′-oxazol]-2′-amine,    (3R*,4S*)-N-(isoquinolin-3-yl)-4′H-1-azaspiro[bicyclo[2.2.1]heptane-3,5′-oxazol]-2′-amine,    (3S,4R)—N-(isoquinolin-3-yl)-4′H-1-azaspiro[bicyclo[2.2.1]heptane-3,5′-oxazol]-2′-amine,    (3R,4S)—N-(isoquinolin-3-yl)-4′H-1-azaspiro[bicyclo[2.2.1]heptane-3,5′-oxazol]-2′-amine,    afford    (3R*,4S*)-N-(thiazolo[5,4-b]pyridin-2-yl)-4′H-1-azaspiro[bicyclo[2.2.1]heptane-3,5′-oxazol]-2′-amine,    (3S,4R)—N-(thiazolo[5,4-b]pyridin-2-yl)-4′H-1-azaspiro[bicyclo[2.2.1]heptane-3,5′-oxazol]-2′-amine,    and    (3R,4S)—N-(thiazolo[5,4-b]pyridin-2-yl)-4′H-1-azaspiro[bicyclo[2.2.1]heptane-3,5′-oxazol]-2′-amine,    (3R,4R)—N-(6-(pyridin-4-yl)pyrimidin-4-yl)-4′H-1-azaspiro[bicyclo[2.2.1]heptane-3,5′-oxazol]-2′-amine,    (3R,4R)—N-(6-(1H-imidazol-1-yl)pyrimidin-4-yl)-4′H-1-azaspiro[bicyclo[2.2.1]heptane-3,5′-oxazol]-2′-amine,    (3R,4R)—N-(6-(4-chloro-1H-imidazol-1-yl)pyrimidin-4-yl)-4′H-1-azaspiro[bicyclo[2.2.1]heptane-3,5′-oxazol]-2′-amine,    (3R,4R)—N-(6-(1H-1,2,4-triazol-1-yl)pyrimidin-4-yl)-4′H-1-azaspiro[bicyclo[2.2.1]heptane-3,5′-oxazol]-2′-amine,(3R,4R)—N-(6-(4-methyl-1H-imidazol-1-yl)pyrimidin-4-yl)-4′H-1-azaspiro[bicyclo[2.2.1]heptane-3,5′-oxazol]-2′-amine,    (3R,4R)—N-(5-methoxy-6-(pyrrolidin-1-yl)pyrimidin-4-yl)-4′H-1-azaspiro[bicyclo[2.2.1]heptane-3,5′-oxazol]-2′-amine,    (3R,4R)—N-(benzo[e][1,2,4]triazin-3-yl)-4′H-1-azaspiro[bicyclo[2.2.1]heptane-3,5′-oxazol]-2-amine,    (3R,4R)—N-(5-chlorobenzo[d]oxazol-2-yl)-4′H-1-azaspiro[bicyclo[2.2.1]heptane-3,5′-oxazol]-2′-amine,    (3R,4R)—N-(pyrrolo[1,2f][1,2,4]triazin-4-yl)-4′H-1-azaspiro[bicyclo[2.2.1]heptane-3,5′-oxazol]-2′-amine,    (3R,4R)—N-(thieno[3,2-d]pyrimidin-4-yl)-4′H-1-azaspiro[bicyclo[2.2.1]heptane-3,5′-oxazol]-2′-amine,    (3R,4R)—N-(7-methylthieno[3,2-d]pyrimidin-4-yl)-4′H-1-azaspiro[bicyclo[2.2.1]heptane-3,5′-oxazol]-2′-amine,    (3R,4R)—N-(6-methylbenzo[d]oxazol-2-yl)-4′H-1-azaspiro[bicyclo[2.2.1]heptane-3,5′-oxazol]-2′-amine;    or a pharmaceutically acceptable salt thereof.

For a compound of formula I, including Ia, Ib, Ic, or Id, the scope ofany instance of a variable substituent, including R¹, R², and R³, can beused independently with the scope of any other instance of a variablesubstituent. As such, the invention includes combinations of thedifferent aspects.

Unless specified otherwise, these terms have the following meanings.“Alkyl” means a straight or branched alkyl group composed of 1 to 4carbons. “Alkenyl” means a straight or branched alkyl group composed of2 to 4 carbons with at least one double bond. “Alkynyl” means a straightor branched alkyl group composed of 2 to 4 carbons with at least onetriple bond. “Cycloalkyl” means a monocyclic ring system composed of 3to 7 carbons. “Haloalkyl” and “haloalkoxy” include all halogenatedisomers from monohalo to perhalo. Terms with a hydrocarbon moiety (e.g.alkoxy) include straight and branched isomers for the hydrocarbonportion. Parenthetic and multiparenthetic terms are intended to clarifybonding relationships to those skilled in the art. For example, a termsuch as ((R)alkyl) means an alkyl substituent further substituted withthe substituent R.

The invention includes all pharmaceutically acceptable salt forms of thecompounds. Pharmaceutically acceptable salts are those in which thecounter ions do not contribute significantly to the physiologicalactivity or toxicity of the compounds and as such function aspharmacological equivalents. These salts can be made according to commonorganic techniques employing commercially available reagents. Someanionic salt forms include acetate, acistrate, besylate, bromide,chloride, citrate, fumarate, glucouronate, hydrobromide, hydrochloride,hydroiodide, iodide, lactate, maleate, mesylate, nitrate, pamoate,phosphate, succinate, sulfate, tartrate, tosylate, and xinofoate. Somecationic salt forms include ammonium, aluminum, benzathine, bismuth,calcium, choline, diethylamine, diethanolamine, lithium, magnesium,meglumine, 4-phenylcyclohexylamine, piperazine, potassium, sodium,tromethamine, and zinc.

Some of the compounds of the invention exist in stereoisomeric forms.The invention includes all stereoisomeric forms of the compoundsincluding enantiomers and diastereromers. Methods of making andseparating stereoisomers are known in the art.

The invention includes all tautomeric forms of the compounds. An exampleof a tautomeric pair is shown below.

The invention is intended to include all isotopes of atoms occurring inthe present compounds. Isotopes include those atoms having the sameatomic number but different mass numbers. By way of general example andwithout limitation, isotopes of hydrogen include deuterium and tritium.Isotopes of carbon include ¹³C and ¹⁴C. Isotopically-labeled compoundsof the invention can generally be prepared by conventional techniquesknown to those skilled in the art or by processes analogous to thosedescribed herein, using an appropriate isotopically-labeled reagent inplace of the non-labeled reagent otherwise employed. Such compounds mayhave a variety of potential uses, for example as standards and reagentsin determining biological activity. In the case of stable isotopes, suchcompounds may have the potential to favorably modify biological,pharmacological, or pharmacokinetic properties.

Synthetic Methods

The compounds may be made by methods known in the art including thosedescribed below and including variations within the skill of the art.Some reagents and intermediates are known in the art. Other reagents andintermediates can be made by methods known in the art using readilyavailable materials. The variables (e.g. numbered “R” substituents) usedto describe the synthesis of the compounds are intended only toillustrate how to make the compounds and are not to be confused withvariables used in the claims or in other sections of the specification.The following methods are for illustrative purposes and are not intendedto limit the scope of the invention.

Some of the compounds may be prepared using the reactions and techniquesdescribed in this section. The reactions are performed in solventsappropriate to the reagents and materials employed and are suitable forthe transformations being effected. It is understood by one skilled inthe art of organic synthesis that the functionality present on variousportions of the molecule must be compatible with the reagents andreactions proposed. Such restrictions to the substituents which arecompatible with the reaction conditions will be readily apparent to oneskilled in the art and alternate methods must then be used.

Abbreviations used in the schemes generally follow conventions used inthe art. Chemical abbreviations used in the specification and examplesare defined as follows: “NaHMDS” for sodium bis(trimethylsilyl)amide;“DMF” for N,N-dimethylformamide; “MeOH” for methanol; “NBS” forN-bromosuccinimide; “Ar” for aryl; “TFA” for trifluoroacetic acid; “LAH”for lithium aluminum hydride; “BOC” for t-butoxycarbonyl, “DMSO” fordimethylsulfoxide; “h” for hours; “rt” for room temperature or retentiontime (context will dictate); “min” for minutes; “EtOAc” for ethylacetate; “THF” for tetrahydrofuran; “EDTA” forethylenediaminetetraacetic acid; “Et₂O” for diethyl ether; “DMAP” for4-dimethylaminopyridine; “DCE” for 1,2-dichloroethane; “ACN” foracetonitrile; “DME” for 1,2-dimethoxyethane; “HOBt” for1-hydroxybenzotriazole hydrate; “DIEA” for diisopropylethylamine, “Nf”for CF₃(CF₂)₃SO₂—; and “TMOF” for trimethylorthoformate.

Abbreviations as used herein, are defined as follows: “1×” for once,“2×” for twice, “3×” for thrice, “° C.” for degrees Celsius, “eq” forequivalent or equivalents, “g” for gram or grams, “mg” for milligram ormilligrams, “L” for liter or liters, “mL” for milliliter or milliliters,“μL” for microliter or microliters, “N” for normal, “M” for molar,“mmol” for millimole or millimoles, “min” for minute or minutes, “h” forhour or hours, “rt” for room temperature, “RT” for retention time, “atm”for atmosphere, “psi” for pounds per square inch, “conc.” forconcentrate, “sat” or “sat'd” for saturated, “MW” for molecular weight,“mp” for melting point, “cc” for enantiomeric excess, “MS” or “MassSpec” for mass spectrometry, “ESI” for electrospray ionization massspectroscopy, “HR” for high resolution, “HRMS” for high resolution massspectrometry, “LCMS” for liquid chromatography mass spectrometry, “HPLC”for high pressure liquid chromatography, “RP HPLC” for reverse phaseHPLC, “TLC” or “tlc” for thin layer chromatography, “NMR” for nuclearmagnetic resonance spectroscopy, “¹H” for proton, “δ” for delta, “s” forsinglet, “d” for doublet, “t” for triplet, “q” for quartet, “m” formultiplet, “br” for broad, “Hz” for hertz, and “α”, “β”, “R”, “S”, “E”,and “Z” are stereochemical designations familiar to one skilled in theart.

Some of the compounds of Formula I can be prepared as illustrated inReaction Scheme 1. The ketone of Formula III is known and may beprepared by methods known to those skilled in the art. The ketone can beconverted to the corresponding cyanohydrin of Formula IV by reactionwith sodium or potassium cyanide plus an acid. The compound of FormulaIV can be reduced to the corresponding amino-methyl compound (boranecomplex) of Formula V by reaction with borane/tetrahydrofuran complex.

The compound of Formula V can be reacted with heteroaryl isothiocyanatesdirectly in an inert solvent to give the thioureas of Formula VI.Alternatively, the heteroarylamine can be reacted withthiocarbonyl-diimidazole to give an activated species which can be usedwithout isolation to convert the compound of Formula V to the compoundof Formula VI. The heteroarylamine may be prepared by methods known tothose skilled in the art.

The thiourea of Formula VI can be cyclized using, for example,di-isopropyl carbodiimide to give the oxazoline of Formula VII which maybe deprotected via treatment with acid to give the racemic final productof the compound of Formula I. The compound of Formula I may be resolvedinto pure enantiomer compounds by means known in the art, for example,via chiral chromatography.

Alternatively, the enantiopure ketones of Formula I are known and may beprepared by methods known to those skilled in the art. The enantiopureketone may then be advanced as in Scheme I to provide enantiopureaminoalcohol V.

Alternatively, the borane group of V may be removed with hydrochloricacid to give dihydrochloride salt XII, which can be reacted in thepresence of base with an isothiocyanate to give intermediate thioureaXIII, which can then be cyclized as in Reaction Schemes 1-2 to give I.

Additionally, the (hetero)aromatic amines may be reacted with carbondisulfide, sodium hydroxide, and methyl iodide to give intermediatedimethyl carbonimidodithioates XIV. These are reacted withdihydrochloride XII in the presence of base to eliminate two moles ofmethanethiol and generate desired products I directly.

Biological Methods

-   I) α7 Nicotinic Acetycholine Receptor Binding. Membranes were    prepared for binding using HEK293 cells stably expressing the rat α7    nicotinic acetycholine receptor (rat α7 nAChR). Cells were    homogenized at 4° C. in hypotonic lysis buffer consisting of 10 mM    Tris (pH 7.4), 5 mM EDTA and protease inhibitors and centrifuged at    32000×g for 20 minutes. The pellet was washed once in membrane wash    buffer consisting of 50 mM Tris (pH 7.4), 1 mM EDTA and protease    inhibitors and centrifuged at 32000×g for 20 minutes. This pellet    was then resuspended in assay buffer consisting 50 mM KH₂PO₄ (pH 7.4    at 25° C.), 1 mM EDTA, 0.005% Triton-X 100 and 0.1% (v/v) Sigma    Protease Inhibitor Cocktail. Aliquots were then frozen in dry    ice/ethanol and kept at −80° C. until the day of the assay.-   II) A Ca²⁺-Sensitive, Fluorescence-Based Assay α-7 for Nicotinic    Acetylcholine Receptor Channel Function In Mammalian Cells    (“FLIPR”). Summary: Lead compounds are evaluated for agonist    activity at α-7, α3β4, α4αβ2, and α1β1δ1ε sub-types of nicotinic ACh    receptor ion channels expressed in mammalian HEK 293 cells. Agonist    potency and efficacy values are determined from kinetic fluorescence    Ca²⁺ influx measurements made using a 384 well FLIPR (Fluorescence    Image Plate Reader). The utility of fluorescent indicators for    measuring changes in intracellular divalent cation concentrations,    particularly Ca²⁺, for drug discovery endeavors is well documented    (Rudiger, R., et al., Nature Reviews, 2003, 4:579-586; Gonzalez J.    E., et al., Receptors and Channels, 2002, 8:283-295). In this assay,    channel expressing HEK cell lines seeded in 384 well assay plates    are loaded with a membrane permeant fluorescent Ca²⁺ indicator dye,    whose 510 nm green emission signal increases in response to    elevation of intracellular Ca²⁺ concentration. The basal    fluorescence from the cells is monitored in real time, followed by    the acute addition of test compounds. If the compound is an agonist    at any of the non-selective cation channels, the latter open and    allow the movement of extracellular Ca²⁺ ions into the cell    cytoplasm, where they bind to the Ca²⁺ indicator dye, and produce an    increase in fluorescence output signal , which is detected by a    cooled CCD imaging camera.

Materials and Methods: Reagents: The acetomethoxy (AM) ester of the Ca²⁺indicator dye Fluo-4 was obtained from InVitrogen, (Carlsbad, Calif.).Acetylcholine and all buffer constituents were purchased from SigmaChemical Company, St. Louis, Mo. G418 and Minimal Essential Medium werepurchased from InVitrogen Life Technologies, Carlsbad, Calif. Fetalbovine serum was purchased from (InVitrogen, Carlsbad, Calif.).

Cell Culture: HEK-293 cells were grown in Minimal Essential Mediumcontaining 10% (v/v) fetal bovine serum at 37° C. in a 5% CO₂ incubator.HEK-293 cells stably expressing the ion channels were grown in the samemedium with the addition of 500 μg/ml G418.

Ca²⁺ flux assays of Ca²⁺ channels expressed in HEK-293 cells: HEK-293cells expressing the ion channels of interest were plated in 384 well,black-walled, clear-bottomed, poly-D-lysine coated plates at a densityof ˜20,000 cells/well in 20 μl of Minimal Essential Medium containing10% (v/v) fetal bovine serum and incubated for 2 days at 29° C. in a 5%CO₂ incubator. Prior to assay, cells were loaded with the Fluo-4 AMester. Cell loading was accomplished by removing the culture medium andreplacing it with 30 μl/well of the AM ester of the dye (5 μM) mixedwith Hanks Balanced Salt Solution (#14175-095) containing 20 mM HEPES,2.5 mM probenecid, 0.5 mM CaCl₂, 1 mM MgCl2 and 10 μM atropine. Dyeloading was allowed to proceed for 90 minutes at room temperature atwhich time the dye loading solution was removed and replaced with 40μl/well of Hanks buffer. Cells loaded with dye were loaded onto aFLIPR384 (Molecular Devices, Sunnyvale, Calif.). Fluo-4 dye was excitedusing the 488 nm line of an argon laser. Emission was filtered using a540+/−30 nm bandpass filter. For evaluation of the effects of testcompounds using the Ca²⁺ flux assay, compounds to be tested wereprovided in assay ready plates. For nicotinic receptor ion channelexpressing cells, the assay was initiated by the addition of 20 μl/wellof Hanks buffer containing test compounds. For all assays, data werecollected at 1 Hz for 10 seconds (baseline), at which time the compoundcontaining stimulus buffers are added, and further measurementscollected at 0.33 Hz for 3 min.

Data Analysis: The statistical robustness of the nicotinic receptor Ca²⁺flux assays is determined from blanks and totals wells. The totals wellsdefine maximal channel activation for each compound test plate (Maximumefficacious dose of acetylcholine), and the blanks wells which containmatched DMSO only, define zero channel activation. The raw fluorescenceunits data files generated on the FLIPR plate reader are automaticallyexported and processed by in-house data analysis tools. The reducedpercent activation data for each concentration of test compound are fitusing MathIQ fitting engine (ID Business Solutions Limited, Surrey, UK).Data were analyzed by fitting maximum amplitudes of change influorescence, for Ca²⁺ flux for a given condition of test compound.Potencies (EC₅₀ values) of compounds are calculated from the average ofthree assay wells from a twenty point CRC. Test compound efficacy values(Ymax values) are expressed relative to a maximal response toacetylcholine in the total wells.

-   III) Fos quantification assay: Male Wistar rats are treated with    drug (1-10 mg/kg) or vehicle (2 ml/kg, sc). Two hours after    treatments, the rats are rapidly decapitated and discrete brain    regions of interest are isolated on ice and weighed and flash frozen    with liquid nitrogen and stored at −80 deg. C. Further processing of    the brain tissue for nuclear extracts as well as for Fos    quantification are in accordance with the protocol prescribed by a    commercially available ELISA-based chemiluminiscence detection kit    (catalog #89860, EZ-detect c-Fos Trans kit, Pierce Biotechnology    Inc., Rockford, Ill.).-   IV) MK-801 Disrupted Set-Shift Assay in rats: This assay uses a    modification of the protocol described by Stefani et al. (Behavioral    Neuroscience, 2003, 117: 728-737). Test compounds are assessed for    their ability to reverse an MK-801-induced performance deficit (0.03    mg/kg, i.p., single dose) in this assay.

The activity of specific compounds described herein and tested in theabove assay (II) is provided in Table 1.

TABLE 1

FLIPR α7 FLIPR activity α7-HI rating^(a) Example (EC₅₀, (EC₅₀, Number R₁nM) nM)  1

411 +  2

+  3

91 ++  4

++  5

311 +  6

155 ++  7

+++  7a

+++  7b

+++  8

++  8a

121 ++  8b

+++  9

487 + 10

++ 11

34 +++ 12

+++ 13

++ 14

++ 15

+++ 16

33 +++ 16a

+ 16b

+++ 17

+++ 17a

+ 17b

35 +++ 18

+++ 19

45 +++ 20

129 ++ 21

+++ 22

++ 23

+++ 24

+++ 25

+++ 26

++ 27

++ 28

222 ++ 29

+++ ^(a)Activity based on EC₅₀ nM values: +++ = <100 nM; ++ = 100-1000nM; + = 1000-100000 nM; ^(b)NT = Not tested; NA = Not active (>1000000nM).

Pharmaceutical Compositions and Methods of Treatment

Compounds of formula I bind to alpha 7 and can be useful in treatingaffective disorders and neurodegenerative disorders. Therefore, anotheraspect of the invention is a composition comprising a compound offormula I, including Ia, Ib, Ic, or Id, or a pharmaceutically acceptablesalt thereof, and a pharmaceutically acceptable carrier.

Another aspect of the invention is the use of a compound of formula I,including Ia, Ib, Ic, or Id, in the manufacture of a medicament for thetreatment of affective disorders or neurodegenerative disorders.

Another aspect of the invention is the use of a compound of formula I,including Ia, Ib, Ic, or Id, in the manufacture of a medicament for thetreatment of schizophrenia or Alzheimer's Disease.

Another aspect of the invention is a method of treating affectivedisorders or neurodegenerative disorders comprising administering to apatient a therapeutically effective amount of a compound of formula I,including Ia, Ib, Ic, or Id.

Another aspect of the invention is a method of treating schizophrenia orAlzheimer's Disease comprising administering to a patient atherapeutically effective amount of a compound of formula I, includingIa, Ib, Ic, or Id.

Another aspect of the invention is a method of treating schizophreniacomprising administering to a patient a therapeutically effective amountof a compound of formula I, including Ia, Ib, Ic, or Id.

Another aspect of the invention is a method of treating Alzheimer'sDisease comprising administering to a patient a therapeuticallyeffective amount of a compound of formula I, including Ia, Ib, Ic, orId.

Another aspect of the invention is a method of treating cognitivedisorders comprising administering to a patient a therapeuticallyeffective amount of a compound of formula I, including Ia, Ib, Ic, orId.

Another aspect of the invention is a method of treating rheumatoidarthritis comprising administering to a patient a therapeuticallyeffective amount of a compound of formula I, including Ia, Ib, Ic, orId.

Another aspect of the invention is a method of treating osteoarthritiscomprising administering to a patient a therapeutically effective amountof a compound of formula I, including Ia, Ib, Ic, or Id.

Another aspect of the invention is a method of treating ulcerativecolitis comprising administering to a patient a therapeuticallyeffective amount of a compound of formula I, including Ia, Ib, Ic, orId.

Another aspect of the invention is a method of treating Crohn's Diseasecomprising administering to a patient a therapeutically effective amountof a compound of formula I, including Ia, Ib, Ic, or Id.

Another aspect of the invention is a method of treating diabetescomprising administering to a patient a therapeutically effective amountof a compound of formula I, including Ia, Ib, Ic, or Id.

“Patient” means a person suitable for therapy as understood bypractitioners in the field of affective disorders and neurodegenerativedisorders.

“Treatment,” “therapy,” and related terms are used as understood bypractitioners in the field of affective disorders and neurodegenerativedisorders.

The compounds of this invention are generally given as pharmaceuticalcompositions comprised of a therapeutically effective amount of acompound or its pharmaceutically acceptable salt and a pharmaceuticallyacceptable carrier and may contain conventional excipients.Pharmaceutically acceptable carriers are those conventionally knowncarriers having acceptable safety profiles. Compositions encompass allcommon solid and liquid forms including for example capsules, tablets,losenges, and powders as well as liquid suspensions, syrups, elixers,and solutions. Compositions are made using common formulationtechniques, and conventional excipients (such as binding and wettingagents) and vehicles (such as water and alcohols) are generally used forcompositions. See, for example, Remington's Pharmaceutical Sciences,Mack Publishing Company, Easton, Pa., 17th edition, 1985.

Solid compositions are normally formulated in dosage units andcompositions providing from about 1 to 1000 mg of the active ingredientper dose are preferred. Some examples of dosages are 1 mg, 10 mg, 100mg, 250 mg, 500 mg, and 1000 mg. Generally, other agents will be presentin a unit range similar to agents of that class used clinically.Typically, this is 0.25-1000 mg/unit.

Liquid compositions are usually in dosage unit ranges. Generally, theliquid composition will be in a unit dosage range of 1-100 mg/mL. Someexamples of dosages are 1 mg/mL, 10 mg/mL, 25 mg/mL, 50 mg/mL, and 100mg/mL. Generally, other agents will be present in a unit range similarto agents of that class used clinically. Typically, this is 1-100 mg/mL.

The invention encompasses all conventional modes of administration; oraland parenteral methods are preferred. Generally, the dosing regimen willbe similar to other agents used clinically. Typically, the daily dosewill be 1-100 mg/kg body weight daily. Generally, more compound isrequired orally and less parenterally. The specific dosing regime,however, will be determined by a physician using sound medicaljudgement.

DESCRIPTION OF SPECIFIC EMBODIMENTS

¹H-NMR spectra were run on a Bruker 500, 400, or 300 MHz instrument andchemical shifts were reported in ppm (δ) with reference totetramethylsilane (δ=0.0). All evaporations were carried out underreduced pressure. Unless otherwise stated, LC/MS analyses were carriedout on a Shimadzu instrument using a Phenomenex-Luna 4.6×50 mm S 10reverse phase column employing a flow rate of 4 mL/min using a 0.1% TFAin methanol/water gradient [0-100% in 3 min, with 4 min run time] and aUV detector set at 220 nm or Gemini C18 4.6×50 mm 5 u reverse phasecolumn employing a flow rate of 5 mL/min using a 10 mM ammonium acetateacetonitrile/water gradient [5-95% in 3 min, with 4 min run time] and aUV detector set at 220 nm (negative-ion mass spectrometry). Unlessotherwise stated, purification could be done by preparative C-18 columnemploying gradients of methanol-water containing 0.1% of trifluoroaceticacid (TFA), and using a Shimadzu High Performance Liquid PreparativeChromatographic System employing an XTERRA 30×100 mm S5 column at 40mL/min flow rate with a 12 min gradient.

EXAMPLE 1(3R*,4S*)-N-(6-Methoxybenzo[d]thiazol-2-yl)-4′H-1-azaspiro[bicyclo[2.2.1]heptane-3,5′-oxazol]-2′-amine

Step A:((1R*,3S*,4S*)-3-(Aminomethyl)-3-hydroxy-1-ammoniobicyclo[2.2.1]heptan-1-yl)trihydroborate

To a suspension of(3R*,4S*)-3-hydroxy-1-azabicyclo[2.2.1]heptane-3-carbonitrile, which wassynthesized according to Swain C. J., et. al., Tetrahedron Lett.,31:2445-2448 (1990), in THF (5 mL) was added a solution of boranetetrahydrofuran complex in THF (2.4 mL, 2.4 mmol). The mixture wasstirred at ambient temperature for 20 min, at which time all solids haddissolved. An additional portion of borane tetrahydrofuran complex inTHF (4.7 mL, 4.7 mmol) was added, and the mixture was brought to refluxfor 3.5 h. After this time, the mixture was cooled to ambienttemperature and carefully quenched by the slow dropwise addition of EtOH(5 mL) followed by water (0.5 mL). The mixture was allowed to stir 72 h,at which time it was evaporated to dryness. The resultant oily solid wasazeotroped with MeOH to remove traces of EtOH and water.((1R*,3S*,4S*)-3-(aminomethyl)-3-hydroxy-1-ammoniobicyclo[2.2.1]heptan-1-yl)trihydroborate(420 mg, ˜85% purity, 99% yield) was isolated as a cream colored solidand used without further purification. ¹H NMR (400 MHz, MeOD) δ ppm3.18-3.26 (m, 2H) 2.91-3.02 (m, 1H) 2.63-2.90 (m, 5H) 2.50 (d, J=4.52Hz, 1H) 1.16-2.15 (m, 5H).

Step B: N-(6-Methoxybenzo[d]thiazol-2-yl)-¹H-imidazole-1-carbothioamide

To 6-methoxybenzo[d]thiazol-2-amine (0.53 g, 2.94 mmol) in acetonitrile(20 mL) was added 1,1′-thiocarbonyldiimidazole (0.681 g, 3.82 mmol). Thereaction mixture was stirred at 65° C. for 24 hours. The precipitate wasfiltered and washed with acetonitrile (2×20 mL) to yield the product.The product was taken directly to the next step without any furtherpurification or characterization.

Step C:((1R*,3S*,4S*)-3-Hydroxy-3-((3-(6-methoxybenzo[d]thiazol-2-yl)thioureido)methyl)-1-ammoniobicyclo[2.2.1]heptan-1-yl)trihydroborate

To N-(6-Methoxybenzo[d]thiazol-2-yl)-¹H-imidazole-1-carbothioamide (540mg, 1.86 mmol) in DMF (15 mL) was added((1R*,3S*,4S*)-3-(aminomethyl)-3-hydroxy-1-ammoniobicyclo[2.2.1]heptan-1-yl)trihydroborate(290 mg, 1.86 mmol). The resultant mixture was heated to 70° C. for 3hours. The reaction mixture was cooled to ambient temperature, andpoured into a mixture of EtOAc/Toluene/water (1:1:1) in a separatoryfunnel. The layers were separated and the aqueous phase was extractedtwice more with EtOAc/Toluene (1:1). The combined organics were driedover sodium sulfate, filtered and the solvent was removed in vacuo. Theresidue was suspended in chloroform, and the soluble portion purified bysilica gel chromatography using a 12%-100% EtOAc/Hexanes gradient toyield((1R*,3S*,4S*)-3-hydroxy-3-((3-(6-methoxybenzo[d]thiazol-2-yl)thioureido)methyl)-1-ammoniobicyclo[2.2.1]heptan-1-yl)trihydroborate(375 mg, 53% yield). ¹H NMR (400 MHz, DMSO-d₆) δ ppm 11.78 (br. s., 1H)10.37 (br. s., 1H) 7.41-7.67 (m, 2H) 7.02 (dd, J=8.78, 2.51 Hz, 1H) 5.63(s, 1H) 3.72-3.95 (m, 5H) 3.19 (d, J=9.29 Hz, 1H) 3.01 (dd, J=12.42,1.88 Hz, 1H) 2.76-2.96 (m, 3H) 2.63-2.72 (m, 1H) 1.81-1.99 (m, 1H)1.23-1.82 (m, 4H). LC/MS confirmed product with loss of BH₃ in the LC/MSconditions: retention time 2.27; (M+1-BH₃=365.07).

Step D:(3R*,4S*)-N-(6-Methoxybenzo[d]thiazol-2-yl)-4′H-1-azaspiro[bicyclo[2.2.1]heptane-3,5′-oxazol]-2′-amine

To a suspension of((1R*,3S*,4S*)-3-hydroxy-3-((3-(6-methoxybenzo[d]thiazol-2-yl)thioureido)methyl)-1-ammoniobicyclo[2.2.1]heptan-1-yl)trihydroborate(375 mg, 0.99 mmol) in DMF (5 mL) was added N,N′-diisopropylcarbodiimide(0.46 mL, 2.97 mmol). The mixture was heated to 70° C. for 18 hours,cooled to ambient temperature, poured into EtOAc and washed thrice with1N HCl. TLC showed the UV active component to be in the acid layer. Thecombined acidic extracts were made alkaline by the addition of 1N NaOH,combined with the initial EtOAc layer, and re-extracted withEtOAc/Toluene (2:1). The organics were washed thrice with water and oncewith brine, dried over sodium sulfate, filtered and evaporated in vacuo.The crude solid was purified by silica gel chromatography, employing agradient of 2-20% (10% NH4OH/MeOH)/Chloroform. The title compound wasisolated as a yellow oil;(3R*,4S*)-N-(6-methoxybenzo[d]thiazol-2-yl)-4′H-1-azaspiro[bicyclo[2.2.1]heptane-3,5′-oxazol]-2′-amine(90 mg, 25% yield). ¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 9.25 (br. s.,1H) 7.53 (d, J=8.78 Hz, 1H) 7.18 (d, J=2.51 Hz, 1H) 6.94 (dd, J=8.78,2.51 Hz, 1H) 4.12 (d, J=9.54 Hz, 1H) 3.81-3.87 (m, 3H) 3.75 (d, J=9.54Hz, 1H) 3.31 (dd, J=13.55, 2.01 Hz, 1H) 3.09 (d, J=10.04 Hz, 1H)2.82-2.94 (m, 1H) 2.81 (d, J=4.52 Hz, 1H) 2.66 (dd, J=13.68, 2.89 Hz,1H) 2.43-2.56 (m, 2H) 1.68-1.81 (m, 1H) 1.29-1.43 (m, J=7.81, 7.81,5.46, 2.26 Hz, 1H). MS (LC/MS) R.T.=0.96; [M+H]⁺=330.95.

EXAMPLE 2(3R*,4R*)-N-(6-Methoxybenzo[d]thiazol-2-yl)-4′H-1-azaspiro[bicyclo[2.2.1]heptane-3,5′-oxazol]-2′-amine

Step A:((1S*,3S*,4R*)-3-(Aminomethyl)-3-hydroxy-1-ammoniobicyclo[2.2.1]heptan-1-yl)trihydroborate

(3R*,4R*)-3-hydroxy-1-azabicyclo[2.2.1]heptane-3-carbonitrile (305 mg,2.2 mmol), which was synthesized according to Swain C. J., et. al.,Tetrahedron Lett., 31:2445-2448 (1990), was reacted according to themethod of EXAMPLE 1, STEP A to provide((1R*,3S*,4R*)-3-(aminomethyl)-3-hydroxy-1-ammoniobicyclo[2.2.1]heptan-1-yl)trihydroborate(404 mg, ˜85% purity, 99% yield) was isolated as a cream colored solidand used without further purification.

¹H NMR (400 MHz, MeOD) δ ppm 3.02-3.19 (m, 1H) 2.46-3.02 (m, 8H)2.27-2.42 (m, 1H) 1.23-2.04 (m, 4H).

Step C:((1S*,3S*,4R*)-3-Hydroxy-3-((3-(6-methoxybenzo[d]thiazol-2-yl)thioureido)methyl)-1-ammoniobicyclo[2.2.1]heptan-1-yl)trihydroborate

N-(6-Methoxybenzo[d]thiazol-2-yl)-¹H-imidazole-1-carbothioamide (186 mg,0.64 mmol) and((1S*,3S*,4R*)-3-(aminomethyl)-3-hydroxy-1-ammoniobicyclo[2.2.1]heptan-1-yl)trihydroborate(100 mg, 0.64 mmol) were reacted according to the method of EXAMPLE 1,STEP C to yield((1S*,3S*,4R*)-3-hydroxy-3-((3-(6-methoxybenzo[d]thiazol-2-yl)thioureido)methyl)-1-ammoniobicyclo[2.2.1]heptan-1-yl)trihydroborate(106 mg, 44% yield). ¹H NMR (400 MHz, DMSO-d₆) δ ppm 11.72 (br. s., 1H)10.27 (br. s., 1H) 7.31-7.69 (m, 2H) 7.01 (dd, J=8.78, 2.51 Hz, 1H) 5.56(br. s., 1H) 3.91 (dd, J=13.68, 5.90 Hz, 1H) 3.65-3.83 (m, 4H) 2.80-3.08(m, 4H) 2.74 (d, J=7.03 Hz, 1H) 2.51-2.59 (m, 2H) 2.10-2.25 (m, 1H)1.71-1.87 (m, 1H) 1.49 (br. s., 3H). MS (LC/MS) R.T.=2.91; (M−1=377.2).

Step D:((1S*,3S*,4R*)-2′-(6-Methoxybenzo[d]thiazol-2-ylamino)-4′H-1-ammoniospiro[bicyclo[2.2.1]heptane-3,5′-oxazole]-1-yl)trihydroborate

To a suspension of((1S*,3S*,4R*)-3-hydroxy-3-((3-(6-methoxybenzo[d]thiazol-2-yl)thioureido)methyl)-1-ammoniobicyclo[2.2.1]heptan-1-yl)trihydroborate(105 mg, 0.28 mmol) in DMF (2 mL) was added N,N′-diisopropylcarbodiimide(0.13 mL, 0.83 mmol). The mixture was heated to 70° C. for 18 hours,cooled to ambient temperature and poured into toluene/water. The phaseswere separated and the organics were washed twice with water. Theorganic phase was concentrated in vacuo to give a residue that was thenpurified by silica gel chromatography using a 12%-100% EtOAc/Hexanesgradient to yield((1S*,3S*,4R*)-2′-(6-methoxybenzo[d]thiazol-2-ylamino)-4′H-1-ammoniospiro[bicyclo[2.2.1]heptane-3,5′-oxazole]-1-yl)trihydroborate(42 mg, 44% yield) as a white solid. ¹H NMR (400 MHz, CHLOROFORM-d) δppm 9.32 (br. s., 1H) 7.52 (d, J=8.78 Hz, 1H) 7.17 (d, J=2.51 Hz, 1H)6.93 (dd, J=8.91, 2.64 Hz, 1H) 3.92 (d, J=9.54 Hz, 1H) 3.81 (s, 3H) 3.78(d, 1H) 3.16-3.31 (m, 3H) 2.99-3.10 (m, 1H) 2.91-2.98 (m, 1H) 2.80-2.89(m, 2H) 2.42-2.55 (m, 1H) 1.90-2.01 (m, 1H) 1.46 (br. s., 3H). LC/MSconfirmed product with loss of BH₃ in the LC/MS conditions: retentiontime 1.96; (M+1-BH₃=331.3).

Step D:(3R*,4R*)-N-(6-Methoxybenzo[d]thiazol-2-yl)-4′H-1-azaspiro[bicyclo[2.2.1]heptane-3,5′-oxazol]-2′-amine

To a suspension of((1S*,3S*,4R*)-2′-(6-methoxybenzo[d]thiazol-2-ylamino)-4′H-1-ammoniospiro[bicyclo[2.2.1]heptane-3,5′-oxazole]-1-yl)trihydroborate(42 mg, 0.12 mmol) in acetone (5 mL) was added dropwise 3.0N HCl (5 mL,15.0 mmol). The effervescent mixture was allowed to stir at ambienttemperature for 3 hours, at which time, bubbling had subsided. Thesolution was poured into a separatory funnel containing chloroform andthe phases were separated. The acidic aqueous layer was washed once morewith chloroform, and then carefully made alkaline by the addition ofsodium bicarbonate and 1N NaOH. The alkaline aqueous phase was extractedtwice with chloroform, dried over sodium sulfate, filtered and thesolvent removed in vacuo. The resultant white solid was pure(3R*,4R*)-N-(6-methoxybenzo[d]thiazol-2-yl)-4′H-1-azaspiro[bicyclo[2.2.1]heptane-3,5′-oxazol]-2′-amine(33 mg, 79% yield). ¹H NMR (400 MHz, MeOD) δ ppm 7.52 (d, J=8.78 Hz, 1H)7.25 (d, J=2.51 Hz, 1H) 6.91 (dd, J=8.91, 2.64 Hz, 1H) 3.89 (d, J=10.04Hz, 1H) 3.78 (s, 3H) 3.68 (d, J=10.04 Hz, 1H) 2.83-3.00 (m, 3H)2.65-2.80 (m, 3H) 2.55 (dd, J=10.29, 3.76 Hz, 1H) 2.07-2.17 (m, 1H)1.57-1.70 (m, 1H). MS (LC/MS) R.T.=2.56; [M+H]⁺=331.28.

EXAMPLE 3(3R*,4R*)-N-(5-Chlorothiazolo[5,4-b]pyridin-2-yl)-4′H-1-azaspiro[bicyclo[2.2.1]heptane-3,5′-oxazol]-2′-amine

Step A: Dimethyl 5-chlorothiazolo[5,4-b]pyridin-2-ylcarbonimidodithioate

To a suspension of 5-chlorothiazolo[5,4-b]pyridin-2-amine (930 mg, 5.00mmol) in DMF (5 mL) was added 20.0M sodium hydroxide (500 μL, 10.00mmol). The mixture was allowed to stir 10 min at room temperature atwhich time carbon disulfide was added (750 μL, 12.50 mmol) and themixture was stirred for 10 minutes. An additional portion of 20.0Msodium hydroxide (500 μL, 10.0 mmol) was added and the mixture was againstirred for 10 minutes. Finally, iodomethane (750 μL, 12.00 mmol) wasadded dropwise. An exotherm was noticed during this addition. Themixture was stirred for 15 minutes, at which time a voluminousprecipitate had formed. The mixture was poured into water and the solidswere collected by filtration. Most of the collected solids were paleyellow and crystalline. A few small clumps of a slightly darker gummyorange solid were also present, and these were manually removed anddiscarded. The remainder was the title compound, dimethyl5-chlorothiazolo[5,4-b]pyridin-2-ylcarbonimidodithioate (1.00 g, 69%yield). 1H NMR (400 MHz, CDCl₃) δ ppm 8.04 (d, J=8.53 Hz, 1H) 7.38 (d,J=8.53 Hz, 1H) 2.66 (s, 6H).

Step B:((1S*,3S*,4R*)-2′-(5-Chlorothiazolo[5,4-b]pyridin-2-ylamino)-4′H-1-ammoniospiro[bicyclo[2.2.1]heptane-3,5′-oxazole]-1-yl)trihydroborate

To dimethyl 5-chlorothiazolo[5,4-b]pyridin-2-ylcarbonimidodithioate (139mg, 0.481 mmol) in N,N-dimethylformamide (2 mL) was added((1R*,3S*,4R*)-3-(aminomethyl)-3-hydroxy-1-ammoniobicyclo[2.2.1]heptan-1-yl)trihydroborate(75 mg, 0.481 mmol). The reaction was heated at 100° C. for 1 hour andthen cooled to room temperature. The reaction was poured into water (10mL) and the resulting precipitate was collected to give((1S*,3S*,4R*)-2′-(5-chlorothiazolo[5,4-b]pyridin-2-ylamino)-4′H-1-ammoniospiro[bicyclo[2.2.1]heptane-3,5′-oxazole]-1-yl)trihydroborate(83 mg, 49% yield). MS (LC/MS) R.T.=1.74; [M−H]⁺=348.14.

Step C:(3R*,4R*)-N-(5-Chlorothiazolo[5,4-b]pyridin-2-yl-4′H-1-azaspiro[bicyclo[2.2.1]heptane-3,5′-oxazol]-2′-amine

To a solution of(2′-(5-chlorothiazolo[5,4-b]pyridin-2-ylamino)-4′H-1-ammoniospiro[bicyclo[2.2.1]heptane-3,5′-oxazole]-1-yl)trihydroborate(83 mg, 0.24 mmol) in acetone (1 mL) was added 3M hydrochloric acid(1.42 mL, 4.27 mmol). The reaction was stirred at room temperature for 3hours and then poured into a solution of chloroform and saturated sodiumbicarbonate. The chloroform layer was collected and then washed withwater. The combined organic layers were concentrated in vacuo and thentritrated in diethyl ether (15 mL) to give a white precipitate. Theprecipitate was collected via vacuum filtration to give(3R*,4R*)-N-(5-chlorothiazolo[5,4-b]pyridin-2-yl)-4′H-1-azaspiro[bicyclo[2.2.1]heptane-3,5′-oxazol]-2′-amine(38 mg, 47% yield) 1H NMR (400 MHz, DMSO-d₆) δ ppm 9.30 (br. S., 1H)7.95 (d, J=8.53 Hz, 1H) 7.47 (d, J=8.28 Hz, 1H) 3.93 (d, J=10.29 Hz, 1H)3.80 (d, J=10.29 Hz, 1H) 3.29-3.41 (m, 2H) 3.10-3.24 (m, 2H) 3.06 (d,J=9.29 Hz, 1H) 2.97 (d, J=3.76 Hz, 1H) 2.90 (dd, J=9.79, 3.01 Hz, 1H)2.00-2.15 (m, 1H) 1.72-1.88 (m, 1H). MS (LC/MS) R.T.=1.28; [M+H]⁺=334.2.

EXAMPLE 4(3R*,4R*)-N-(5-Fluorothiazolo[5,4-b]pyridin-2-yl)-4′H-1-azaspiro[bicyclo[2.2.1]heptane-3,5′-oxazol]-2′-amine

Step A: 5-Fluorothiazolo[5,4-b]pyridin-2-amine

6-Fluoropyridin-3-amine (4 g, 35.7 mmol) was added to a mechanicallystirred suspension of potassium rhodanate (27.7 g, 285 mmol) in aceticacid (89 mL) at 0° C. The flask 3-neck flask was then fitted with anaddition funnel charged with bromine (5.70 mL, 111 mmol) in acetic acid(29.7 mL). The bromine solution was added over 30 min and the solutionturned into a viscous and yellow mixture. After bromine addition wascomplete, the reaction mixture was allowed to warm to ambienttemperature and stirred at that temperature for 16 h. Water (30 mL) wasadded to the reaction mixture and it was heated to 85° C. for 20 minbefore the solids were filtered and washed with water and methanol togive 5-fluorothiazolo[5,4-b]pyridin-2-amine (4.18 g, 24.71 mmol, 69.2%yield) as a yellow solid.

Step B: Dimethyl 5-fluorothiazolo[5,4-b]pyridin-2-ylcarbonimidodithioate

5-Fluorothiazolo[5,4-b]pyridin-2-amine (2.0 g, 11.8 mmol) was reactedaccording to the method of EXAMPLE 3, STEP A to provide dimethyl5-fluorothiazolo[5,4-b]pyridin-2-ylcarbonimidodithioate (2.17 g, 67%yield) as a yellow solid. ¹H NMR (500 MHz, chloroform-d) δ ppm 8.14 (dd,J=8.55, 7.02 Hz, 1H) 6.98 (dd, J=8.70, 1.98 Hz, 1H) 2.63 (s, 6H).

Step C: (3S*,4R*)-3-(Aminomethyl)-1-azabicyclo[2.2.1]heptan-3-oldihydrochloride

((1S*,3S*,4R*)-3-(Aminomethyl)-3-hydroxy-1-ammoniobicyclo[2.2.1]heptan-1-yl)trihydroborate(2.6 g, 16.7 mmol) was suspended in acetone (50 mL) and 3N HCl (50 mL,150 mmol) was added dropwise. The effervescent solution was allowed tostir at ambient temperature for 2 hours at which time bubbling hadceased. The solution was evaporated to dryness, azeotroped with EtOH andtriturated with ether/EtOH. The resultant solids were collected byfiltration to give(3S*,4R*)-3-(aminomethyl)-1-azabicyclo[2.2.1]heptan-3-ol dihydrochloride(1.3 g, 36% yield) as a white solid.

Step D:(3R*,4R*)-N-(5-Fluorothiazolo[5,4-b]pyridin-2-yl)-4′H-1-azaspiro[bicyclo[2.2.1]heptane-3,5′-oxazol]-2′-amine

To a solution of dimethyl5-fluorothiazolo[5,4-b]pyridin-2-ylcarbonimidodithioate (95 mg, 0.349mmol) in N,N-dimethylformamide (2 mL) was added(3S*,4R*)-3-(aminomethyl)-1-azabicyclo[2.2.1]heptan-3-ol dihydrochloride(75 mg, 0.349 mmol). The reaction was then treated with cesium carbonate(114 mg, 0.7 mmol). The reaction was heated to 100° C. for 1 hour andthen cooled to room temperature. The reaction was diluted with water (20mL) and chloroform (2×20 mL). The organic phases were combined andconcentrated to residue in vacuo. The residue was then triturated indiethyl ether to give(3R*,4R*)-N-(5-fluorothiazolo[5,4-b]pyridin-2-yl)-4′H-1-azaspiro[bicyclo[2.2.1]heptane-3,5′-oxazol]-2′-amineas a precipitate (42 mg, 37%) that was collected via vacuum filtration.¹H NMR (400 MHz, DMSO-d₆) δ ppm 9.13 (br. s., 1H) 8.07 (dd, J=8.53, 7.28Hz, 1H) 7.16 (dd, J=8.53, 1.51 Hz, 1H) 3.85 (d, J=10.29 Hz, 1H) 3.66 (d,J=10.29 Hz, 1H) 2.77-2.98 (m, 2H) 2.71 (td, J=6.65, 4.02 Hz, 2H)2.58-2.67 (m, 2H) 2.40 (dd, J=10.16, 3.64 Hz, 1H) 1.87-2.00 (m, 1H) 1.53(t, J=4.39 Hz, 1H). MS (LC/MS) R.T.=0.675 min; (M+H=320.1).

EXAMPLE 5(3R*,4R*)-N-(5-Methoxythiazolo[5,4-b]pyridin-2-yl)-4′H-1-azaspiro[bicyclo[2.2.4]heptane-3,5′-oxazol]-2′-amine

Step A: Dimethyl5-methoxythiazolo[5,4-b]pyridin-2-ylcarbonimidodithioate

5-Methoxythiazolo[5,4-b]pyridin-2-amine (1.5 g, 8.3 mmol) was reactedaccording to the method of EXAMPLE 3, STEP A to provide dimethyl5-methoxythiazolo[5,4-b]pyridin-2-ylcarbonimidodithioate (1.72 g, 73%yield) as an orange solid. ¹H NMR (400 MHz, chloroform-d) δ ppm 7.99 (d,J=8.78 Hz, 1H) 6.81 (d, J=8.53 Hz, 1H) 4.01 (s, 3H) 2.65 (s, 6H).

Step B:(3R*,4R*)-N-(5-Methoxythiazolo[5,4-b]pyridin-2-yl)-4′H-1-azaspiro[bicyclo[2.2.1]heptane-3,5′-oxazol]-2′-amine

Dimethyl 5-methoxythiazolo[5,4-b]pyridin-2-ylcarbonimidodithioate wasreacted according to the method of EXAMPLE 4, STEP D to provide(3R*,4R*)-N-(5-methoxythiazolo[5,4-b]pyridin-2-yl)-4′H-1-azaspiro[bicyclo[2.2.1]heptane-3,5′-oxazol]-2′-amine.¹H NMR (400 MHz, DMSO-d₆) δ ppm 8.98 (br. s., 1H) 7.87 (d, J=8.78 Hz,1H) 6.82 (d, J=8.78 Hz, 1H) 3.89 (s, 3H) 3.83 (d, J=10.04 Hz, 1H) 3.64(d, J=10.04 Hz, 1H) 2.56-2.94 (m, 6H) 2.39 (dd, J=10.04, 3.76 Hz, 1H)1.87-1.99 (m, 1H) 1.52 (t, J=4.52 Hz, 1H). MS (LC/MS) R.T.=0.715 min;(M+H=322.2).

EXAMPLE 6(3R*,4R*)-N-(3,5-Dichloropyridin-2-yl)-4′H-1-azaspiro[bicyclo[2.2.4]heptane-3,5′-oxazol]-2′-amine

Step A: 3,5-Dichloro-2-isothiocyanatopyridine

To 3,5-dichloropyridin-2-amine (0.36 g, 2.209 mmol) in dichloromethane(25 mL) was added 1,1′-thiocarbonyldipyridin-2(1H)-one (0.523 g, 2.253mmol). The reaction was stirred at 40° C. for 3 hours. The reaction wascooled to room temperature and the crude was purified by chromatography(Biotage: 25-100% ethyl acetate/hexane) to yield to yield3,5-dichloro-2-isothiocyanatopyridine (0.4 g, 1.951 mmol, 88% yield). ¹HNMR (500 MHz, DMSO-D6) δ ppm 8.50 (t, J=2.59 Hz, 1H), 8.45 (t, J=2.59Hz, 1H). MS (LC/MS) R.T.=2.07; [M+H]⁺=204.8.

Step B:(3R*,4R*)-N-(3,5-Dichloropyridin-2-yl)-4′H-1-azaspiro[bicyclo[2.2.1]heptane-3,5′-oxazol]-2′-amine

To a solution of 3,5-dichloro-2-isothiocyanatopyridine (57 mg, 0.279mmol) in N,N-dimethylformamide (2 mL) was added(3S*,4R*)-3-(aminomethyl)-1-azabicyclo[2.2.1]heptan-3-ol dihydrochloride(60 mg, 0.279 mmol). The reaction was treated with cesium carbonate (227mg, 0.697 mmol) and heated to 80° C. After 2 hours, the reaction wasfurther treated with 1,3-diisopropylcarbodiimide (0.152 mL, 0.976 mmol).The reaction was heated at 80° C. for a further 18 hours and then cooledto room temperature. The reaction was poured into chloroform (20 ml) andwater (20 ml). The organic was collected and purified by silica gelchromatography eluting with 5-40% (10% NH4OH/Methanol)/chloroform. Theproduct fractions were collected and concentrated in vacuo followed bytrituration in diethyl ether to yield(3R*,4R*)-N-(3,5-dichloropyridin-2-yl)-4′H-1-azaspiro[bicyclo[2.2.1]heptane-3,5′-oxazol]-2′-amine(42 mg, 0.134 mmol, 48%). ¹H NMR (400 MHz, DMSO-d₆) δ ppm 8.91 (s, 1H)8.16 (d, J=2.26 Hz, 1H) 7.97 (d, J=2.51 Hz, 1H) 3.79 (d, J=10.04 Hz, 1H)3.58 (d, J=9.79 Hz, 1H) 2.71-2.98 (m, 2H) 2.56-2.71 (m, 4H) 2.37 (dd,J=10.04, 3.76 Hz, 1H) 1.83-2.00 (m, 1H) 1.48 (s, 1H). MS (LC/MS)R.T=1.423; (M+H=312.99).

EXAMPLE 7, 7a, 7b(3R*,4R*)-N-(Isoquinolin-3-yl)-4′H-1-azaspiro[bicyclo[2.2.1]heptane-3,5′-oxazol]-2′-amine

Step A: 3-Isothiocyanatoisoquinoline

To a solution of 1,1′-thiocarbonyldipyridin-2(1H)-one (0.805 g, 3.47mmol) in dichloromethane at room temperature was addedisoquinolin-3-amine (0.5 g, 3.47 mmol). The reaction was stirred at roomtemperature for 18 hours. The LC/MS showed the desired product peak amajor peak. The deep orange solution was concentrated and filtered. Thefiltrate was purified by silica gel chromatography (0-40% ethylacetate-hexanes) to afford4-isothiocyanato-6-(3-methoxyphenyl)pyrimidine (0.55 g, 2.96 mmol, 85%yield) a white solid. LCMS R.T.=2.47; [M+H]⁺=187.23.

Step B:(3R*,4R*)-N-(Isoquinolin-3-yl)-4′H-1-azaspiroibicyclo[2.2.1]heptane-3,5′-oxazol]-2′-amine

3-Isothiocyanatoisoquinoline was reacted according to the method ofEXAMPLE 6, STEP B to afford(3R*,4R*)-N-(isoquinolin-3-yl)-4′H-1-azaspiro[bicyclo[2.2.1]heptane-3,5′-oxazol]-2′-amine(154 mg, 0.497 mmol, 61%) ¹H NMR (400 MHz, MeOD) δ ppm 9.03 (s, 1H) 7.94(d, J=8.28 Hz, 1H) 7.74 (d, J=8.03 Hz, 1H) 7.58-7.65 (m, 1H) 7.40-7.48(m, 1H) 7.35 (br. s., 1H) 3.90 (s, 1H) 3.71 (s, 1H) 2.94-3.07 (m, 1H)2.86-2.94 (m, 1H) 2.79 (d, J=3.51 Hz, 4H) 2.57-2.68 (m, 1H) 2.15-2.29(m, 1H) 1.62-1.74 (m, 1H). MS (LC/MS) R.T.=0.61; (M+H=295.2).

This compound was further separated into individual enantiomers using aChiralcel OD-H column, 30×250 mm, Sum with a mobile phase of 20% MeOHwith 0.1% DEA in carbon dioxide monitored at 250 nm. The separated peakswere concentrated in vacuo to yield white powders. The first peak offthe column afforded(3R,4R)—N-(isoquinolin-3-yl)-4′H-1-azaspiro[bicyclo[2.2.1]heptane-3,5′-oxazol]-2′-amine(EXAMPLE 7a, 43.8 mg). ¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 9.02-9.27(m, 1H) 8.96 (s, 1H) 7.86 (d, J=8.03 Hz, 1H) 7.71 (d, J=8.53 Hz, 1H)7.48-7.64 (m, 1H) 7.30-7.48 (m, 2H) 3.84 (d, J=9.03 Hz, 1H) 3.65 (d,J=8.78 Hz, 1H) 2.83-3.03 (m, 3H) 2.67-2.83 (m, 2H) 2.58-2.67 (m, 1H)2.54 (d, J=2.76 Hz, 1H) 2.30 (br. s., 1H). MS (LC/MS) R.T.=0.74;(M+H=295.3).

The second peak off the column afforded(3S,4S)—N-(isoquinolin-3-yl)-4′H-1-azaspiro[bicyclo[2.2.1]heptane-3,5′-oxazol]-2′-amine(EXAMPLE 7b, 44.2 mg). ¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 9.11 (br.s., 1H) 8.96 (s, 1H) 7.86 (d, J=8.28 Hz, 1H) 7.70 (d, J=8.28 Hz, 1H)7.56 (t, J=7.53 Hz, 1H) 7.33-7.41 (m, 2H) 3.84 (d, J=9.03 Hz, 1H) 3.65(d, J=8.78 Hz, 1H) 2.84-3.03 (m, 3H) 2.69-2.84 (m, 2H) 2.59-2.69 (m, 1H)2.56 (br. s., 1H) 2.29 (d, J=5.02 Hz, 1H). MS(LC/MS) R.T.=0.74;(M+H=295.26).

EXAMPLES 8, 8a, 8b(3R*,4R*)-N-(Thiazolo[5,4-b]pyridin-2-yl)-4′H-1-azaspiroibicyclo[2.2.1]heptane-3,5′-oxazol]-2′-amine

Step A: Dimethyl thiazolo[5,4-b]pyridin-2-ylcarbonimidodithioate

To a suspension of thiazolo[5,4-b]pyridin-2-amine (300 mg, 1.98 mmol) inDMF (2 mL) was added 20.0M sodium hydroxide (200 μL, 4.0 mmol). Themixture was allowed to stir 10 min at room temperature at which timecarbon disulfide was added (300 μL, 4.96 mmol) and the resulting reddishbrown mixture was stirred for 10 minutes. An additional portion of 20 Msodium hydroxide (200 μL, 4.0 mmol) was added and the mixture was againstirred for 10 minutes. Finally, iodomethane (300 μL, 4.76 mmol) wasadded dropwise. The mixture was stirred for 5 minutes, at which time avoluminous yellow precipitate had formed. The mixture was poured intowater and the solids were collected by filtration to afford dimethylthiazolo[5,4-b]pyridin-2-ylcarbonimidodithioate (190 mg, 38% yield) as ayellow solid of sufficient purity to use without further purification.¹H NMR (500 MHz, CDCl₃) δ ppm 8.47 (d, J=4.58 Hz, 1H) 8.11 (dd, J=8.24,1.53 Hz, 1H) 7.37 (dd, J=8.24, 4.88 Hz, 1H) 2.66 (s, 6H).

Step B:(3R*,4R*)-N-(Thiazolo[5,4-b]pyridin-2-yl)-4′H-1-azaspiro[bicyclo[2.2.1]heptane-3,5′-oxazol]-2′-amine

Dimethyl thiazolo[5,4-b]pyridin-2-ylcarbonimidodithioate was reactedaccording to the method of EXAMPLE 4, STEP C to afford(3R*,4R*)-N-(thiazolo[5,4-b]pyridin-2-yl)-4′H-1-azaspiro[bicyclo[2.2.1]heptane-3,5′-oxazol]-2′-amineamine (176 mg, 0.584 mmol, 74%). ¹H NMR (400 MHz, DMSO-d₆) δ ppm 9.17(br. s., 1H) 8.25-8.36 (m, 1H) 7.90 (dd, J=8.03, 1.51 Hz, 1H) 7.39 (dd,J=8.03, 4.77 Hz, 1H) 3.86 (d, J=10.29 Hz, 1H) 3.67 (d, J=10.29 Hz, 1H)2.76-2.99 (m, 2H) 2.58-2.76 (m, 4H) 2.40 (dd, J=10.29, 3.76 Hz, 1H) 1.92(d, J=3.01 Hz, 1H) 1.43-1.61 (m, 1H). MS(LC/MS) R.T=0.44; (M+H=302.18).

This compound was further separated into individual enantiomers using aChiralpak AS-H column, 4.6×250 mm, Sum with a mobile phase of 25% MeOHwith 0.1% DEA in carbon dioxide monitored at 220 nm. The separated peakswere concentrated in vacuo to yield white powders. The first peak offthe column afforded(3S,4S)—N-(thiazolo[5,4-b]pyridin-2-yl)-4′H-1-azaspiro[bicyclo[2.2.1]heptane-3,5′-oxazol]-2′-amine(EXAMPLE 8a, 27.1 mg) ¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 9.34 (br. s.,1H) 8.36 (dd, J=4.77, 1.51 Hz, 1H) 7.82 (dd, J=8.16, 1.38 Hz, 1H)7.15-7.35 (m, 1H) 3.93 (d, J=9.54 Hz, 1H) 3.73 (d, J=9.54 Hz, 1H)2.91-3.05 (m, 3H) 2.68-2.84 (m, 2H) 2.50-2.68 (m, 2H) 2.13-2.31 (m, 1H),1.48-1.73 (m, 1H). MS(LC/MS) R.T=0.40; (M+H=302.25).

The second peak off the column yielded(3R,4R)—N-(thiazolo[5,4-b]pyridin-2-yl)-4′H-1-azaspiro[bicyclo[2.2.1]heptane-3,5′-oxazol]-2′-amine(EXAMPLE 8b, 37.2 mg). ¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 9.32 (br.s., 1H) 8.35 (dd, J=4.77, 1.25 Hz, 1H) 7.81 (dd, J=8.16, 1.38 Hz, 1H)7.10-7.34 (m, 1H) 3.84-4.00 (m, 1H) 3.63-3.82 (m, 1H) 2.82-3.11 (m, 3H)2.67-2.83 (m, 2H), 2.48-2.67 (m, 2H) 2.10-2.32 (m, 1H) 1.50-1.74 (m,1H). MS(LC/MS) R.T.=0.45; (M+H=301.95).

EXAMPLE 9(3R*,4R*)-N-(5-m-Tolylpyrimidin-2-yl)-4′H-1-azaspiro[bicyclo[2.2.1]heptane-3,5′-oxazol]-2′-amine

Step A: 2-Isothiocyanato-5-m-tolylpyrimidine

5-m-Tolylpyrimidin-2-amine was reacted according to the method ofEXAMPLE 6, STEP A to afford 2-isothiocyanato-5-m-tolylpyrimidine. MS(LC/MS) R.T.=4.05; (M+H=227.69).

Step B:(3R*,4R*)-N-(5-m-Tolylpyrimidin-2-yl)-4′H-1-azaspiro[bicyclo[2.2.1]heptane-3,5′-oxazol]-2′-amine

2-Isothiocyanato-5-m-tolylpyrimidine was reacted according to the methodof EXAMPLE 6, STEP B to afford(3R*,4R*)-N-(5-m-tolylpyrimidin-2-yl)-4′H-1-azaspiro[bicyclo[2.2.1]heptane-3,5′-oxazol]-2′-amine(25 mg, 15% yield) as a yellow oil. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 9.02(br. s., 1H) 8.83 (s, 2H) 7.45-7.61 (m, 2H) 7.39 (t, J=7.65 Hz, 1H) 7.22(d, J=7.53 Hz, 1H) 3.82 (d, J=10.04 Hz, 1H) 3.62 (d, J=10.04 Hz, 1H)2.55-2.96 (m, 6H) 2.40 (s, 3H) 2.35 (d, J=4.27 Hz, 1H) 1.85-2.04 (m, 1H)1.78-1.85 (m, 1H). MS(LC/MS) R.T.=1.17; (M+H=336.03).

EXAMPLE 10(3R*,4R*)-N-(5-Methoxypyridin-2-yl)-4′H-1-azaspiro[bicyclo[2.2.1]heptane-3,5′-oxazol]-2′-amine

Step A: 2-Isothiocyanato-5-methoxypyridine

5-Methoxypyridin-2-amine was reacted according to the method of EXAMPLE6, STEP A to afford 2-isothiocyanato-5-methoxypyridine, which was usedin the next step without further characterization.

Step B:(3R*,4R*)-N-(5-Methoxypyridin-2-yl)-4′H-1-azaspiro[bicyclo[2.2.1]heptane-3,5′-oxazol]-2′-amine

2-Isothiocyanato-5-methoxypyridine was reacted according to the methodof EXAMPLE 6, STEP B to afford(3R*,4R*)-N-(5-methoxypyridin-2-yl)-4′H-1-azaspiro[bicyclo[2.2.1]heptane-3,5′-oxazol]-2′-amine(56 mg, 36% yield) as a white powder. ¹H NMR (400 MHz, DMSO-d₆) δ ppm7.94 (d, J=3.26 Hz, 1H) 7.34 (dd, J=8.91, 3.14 Hz, 1H) 7.12 (br. s., 1H)3.73-3.89 (m, 4H) 3.69 (d, J=10.79 Hz, 1H) 3.27-3.40 (m, 1H) 2.97-3.26(m, 4H) 2.92 (dd, J=9.66, 3.14 Hz, 1H) 2.82 (d, J=4.02 Hz, 1H) 2.00-2.20(m, 1H) 1.68-1.89 (m, 1H). MS(LC/MS) R.T.=0.28; (M+H=275.06).

EXAMPLE 11(3R,4R)—N-(6-(Pyridin-3-yl)pyrimidin-4-yl)-4′H-1-azaspiro[bicyclo[2.2.1]heptane-3,5′-oxazol]-2′-amine

Step A: 6-(Pyridin-3-yl)pyrimidin-4-amine

A mixture of 6-chloropyrimidin-4-amine (0.324 g, 2.5 mmol),pyridin-3-ylboronic acid (0.385 g, 3.13 mmol), Na₂CO₃ (0.795 g, 7.5mmol) and bis(triphenylphosphine)palladium(II) chloride (0.035 g, 0.05mmol) were suspended in a mixture of dioxane/EtOH/water. The mixture washeated in the microwave synthesizer at 125° C. for 20 min (reaction wasrun twice) and concentrated. The residue was purified on by silica gelchromatography using a 10-60% ethyl acetate/hexanes gradient, followedby a 5-25% 9:1 methanol:ammonium hydroxide in ethyl acetate gradient.The desired fractions were concentrated to give an off-white solid.MS(LC/MS) R.T.=0.28; (M+H=173.13).

Step B: Dimethyl 6-(pyridin-3-yl)pyrimidin-4-ylcarbonimidodithioate

6-(Pyridin-3-yl)pyrimidin-4-amine was reacted according to the method ofEXAMPLE 3, STEP A to provide dimethyl6-(pyridin-3-yl)pyrimidin-4-ylcarbonimidodithioate, which was used inthe next step without further characterization.

Step C: (3R,4R)-3-Hydroxy-1-azabicyclo[2.2.1]heptane-3-carbonitrile

(R)-1-Azabicyclo[2.2.1]heptan-3-one (2.4 g, 4.9 mmol) which was preparedaccording to Boelsterli, J., et. al., Helvetica Chimica Acta.,75:507-512 (1992), was dissolved in water (2 mL) and cooled on anice-water bath. To this was added a solution of sodium cyanide (260 mg,5.4 mmol) in water (1 mL). After 15 minutes, the voluminous precipitatethat formed was collected by filtration to afford(3R,4R)-3-hydroxy-1-azabicyclo[2.2.1]heptane-3-carbonitrile as an offwhite solid (397 mg, 59% yield). ¹H NMR (400 MHz, DMSO-d₆) δ ppm 6.70(s, 1H) 3.22-3.39 (m, 1H) 3.08 (dd, J=12.80, 2.01 Hz, 1H) 2.83 (d,J=4.02 Hz, 1H) 2.69-2.79 (m, J=11.42, 11.42, 4.77, 2.01 Hz, 1H) 2.66 (d,J=10.54 Hz, 1H) 2.42-2.50 (m, 1H) 2.38 (dd, J=12.92, 3.64 Hz, 1H)1.78-1.94 (m, 1H) 1.43 (tt, J=11.45, 4.74 Hz, 1H).

Step D: (3S,4R)-3-(Aminomethyl)-1-azabicyclo[2.2.1]heptan-3-oldihydrochloride

(3R,4R)-3-Hydroxy-1-azabicyclo[2.2.1]heptane-3-carbonitrile (390 mg,2.82 mmol) was dissolved in THF (1 mL). Borane-THF complex was added(2.9 ml, 2.90 mmol) and the mixture was allowed to stir for 20 min, atwhich time an additional portion of Borane-THF complex (5.7 ml, 5.70mmol) was added and the mixture brought to reflux for 3 h. The reactionmixture was cooled to ambient temperature and carefully quenched with 5ml EtOH followed by 0.5 ml water and allowed to stir overnight. Themixture was evaporated to dryness and azeotroped with EtOH, re-dissolvedin acetone (10 mL) and to this was carefully added 3N HCl (10 mL, 30mmol). The effervescent reaction was allowed to stir for 2 hours, atwhich time bubbling had ceased and the reaction was evaporated tonear-dryness and azeotroped several times with EtOH, at which point theproduct began to crystallize from solution. After ˜5 cycles ofazeotroping, the residue was suspended in EtOH and solids were collectedby filtration to afford(3S,4R)-3-(aminomethyl)-1-azabicyclo[2.2.1]heptan-3-ol dihydrochloride.¹H NMR (400 MHz, DMSO-d₆) δ ppm 11.02 (br. s., 1H) 8.27 (br. s., 3H)6.29 (s, 1H) 2.86-3.63 (m, 9H) 2.14-2.37 (m, 1H) 1.64-2.05 (m, 1H).Optical rotation (4.01 mg/mL, water)=−15.01°.

Step E:(3R,4R)—N-(6-(Pyridin-3-yl)pyrimidin-4-yl)-4′H-1-azaspiro[bicyclo[2.2.1]heptane-3,5′-oxazol]-2′-amine

To a solution of dimethyl6-(pyridin-3-yl)pyrimidin-4-ylcarbonimidodithioate(39 mg, 0.139 mmol) inN,N-dimethylformamide (1 mL) was added(3S,4R)-3-(aminomethyl)-1-azabicyclo[2.2.1]heptan-3-ol, 2 HCl (30 mg,0.139 mmol). The reaction was then treated with cesium carbonate (136mg, 0.4 mmol). The reaction was heated to 100° C. for 3 hour and thencooled to room temperature. The reaction was diluted with water (10 mL)and chloroform (2×20 mL). The organic layers were combined andconcentrated to residue in vacuo. The residue was then purified bysilica gel chromatography eluting with 5%-40% (10%NH4OH/Methanol)/chloroform. The product fractions were collected andconcentrated to give(3R,4R)—N-(6-(pyridin-3-yl)pyrimidin-4-yl)-4′H-1-azaspiro[bicyclo[2.2.1]heptane-3,5′-oxazol]-2′-amineas a yellow solid (15.4 mg, 34% yield). ¹H NMR (500 MHz, DMSO-d₆) δ ppm9.30 (br. s., 2H) 8.85 (s, 1H) 8.70 (d, J=3.36 Hz, 1H) 8.47 (d, J=7.32Hz, 1H) 7.56 (dd, J=7.63, 4.88 Hz, 1H) 7.42 (br. s., 1H) 3.85 (d, J=9.77Hz, 1H) 3.66 (d, J=10.07 Hz, 1H) 2.71-2.96 (m, 2H) 2.55-2.73 (m, 4H)2.37 (dd, J=9.77, 3.66 Hz, 1H) 1.89 (br. s., 1H) 1.48 (t, J=4.58 Hz,1H). MS(LC/MS) R.T=0.19; (M+H=323.1).

EXAMPLE 12(3R,4R)—N-(Benzo[d]thiazol-2-yl)-4′H-1-azaspiro[bicyclo[2.2.1]heptane-3,5′-oxazol]-2′-amine

Step A: Dimethyl benzo[d]thiazol-2-ylcarbonimidodithioate

Benzo[d]thiazol-2-amine was reacted according to the method of EXAMPLE3, STEP A to afford dimethyl benzo[d]thiazol-2-ylcarbonimidodithioate.¹H NMR (400 MHz, DMSO-d₆) δ ppm 7.99 (d, J=7.28 Hz, 1H) 7.83 (d, J=8.28Hz, 1H) 7.47 (td, J=7.72, 1.38 Hz, 1H) 7.28-7.42 (m, 1H) 2.63 (s, 6H).

Step B:(3R,4R)—N-(Benzo[d]thiazol-2-yl)-4′H-1-azaspiro[bicyclo[2.2.4]heptane-3,5′-oxazol]-2′-amine

Dimethyl benzo[d]thiazol-2-ylcarbonimidodithioate was reacted accordingto the method of EXAMPLE 11, STEP E to give(3R,4R)—N-(benzo[d]thiazol-2-yl)-4′H-1-azaspiro[bicyclo[2.2.1]heptane-3,5′-oxazol]-2′-amineas a white powder (8.7 mg, 9.3% yield). ¹H NMR (400 MHz, DMSO-d₆) δ ppm9.11 (br. s., 1H) 7.81 (d, J=7.28 Hz, 1H) 7.63 (d, J=7.53 Hz, 1H)7.28-7.43 (m, 1H) 7.08-7.27 (m, 1H) 3.85 (d, J=10.04 Hz, 1H) 3.66 (d,J=10.29 Hz, 1H) 2.75-3.00 (m, 2H) 2.55-2.74 (m, 4H) 2.39 (dd, J=10.16,3.64 Hz, 1H) 1.92 (t, J=8.78 Hz, 1H) 1.42-1.65 (m, 1H) MS(LC/MS).R.T.=1.50; (M+H=301.00).

EXAMPLE 13(3R,4R)—N-(6-Methoxypyrimidin-4-yl)-4′H-1-azaspiro[bicyclo[2.2.1]heptane-3,5′-oxazol]-2′-amine

Step A: 4-Isothiocyanato-6-methoxypyrimidine

To a bright orange solution of 1,1′-thiocarbonyldipyridin-2(1H)-one(1.86 g, 7.99 mmol) in dichloromethane at room temperature was added6-methoxypyrimidin-4-amine (1 g, 8 mmol). The orange solution wasstirred at room temperature for 18 hours. The LC/MS showed the desiredproduct as one of the major peaks. The deep orange solution wasconcentrated and the remaining residue was filtered. The filtrate waspurified by silica gel chromatography (10-50% ethyl acetate/hexanes) toafford 4-isothiocyanato-6-methoxypyrimidine (0.72 g, 4.3 mmol, 54%yield) as a yellow oil. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 8.49 (1H, d,J=5.79 Hz), 6.95 (1H, d, J=5.79 Hz), 3.92 (3H, s). MS (LC/MS) R.T.=3.15;[M+H]⁻=168.1.

Step B:1-(((3S,4R)-3-Hydroxy-1-azabicyclo[2.2.1]heptan-3-yl)methyl)-3-(6-methoxypyrimidin-4-yl)thiourea

To a solution of 4-isothiocyanato-6-methoxypyrimidine (50.5 mg, 0.30mmol) in N,N-dimethylformamide (2 mL) was added(3S,4R)-3-(aminomethyl)-1-azabicyclo[2.2.1]heptan-3-ol, 2 HCl (50 mg,0.232 mmol). The reaction was treated with cesium carbonate (227 mg,0.697 mmol) and heated to 80° C. After 2 hours, the reaction was cooledto room temperature. The reaction was then purified by silica gelchromatography eluting with 5%-40% (10% NH₄OH/methanol)/chloroform. Theproduct fractions were collected and concentrated to a residue that wasidentified as1-(((3S,4R)-3-hydroxy-1-azabicyclo[2.2.1]heptan-3-yl)methyl)-3-(6-methoxypyrimidin-4-yl)thioureaby LC/MS (R.T.=0.52; (M+H=310.3)). This residue was carried on to thenext step without further analysis.

Step C:(3R,4R)—N-(6-Methoxypyrimidin-4-yl)-4′H-1-azaspiro[bicyclo[2.2.1]heptane-3,5′-oxazol]-2′-amine

The thiourea from the previous step was once again dissolved inN,N-dimethylformamide (2 mL) and treated with1,3-diisopropylcarbodiimide (0.72 mL, 0.465 mmol). The reaction washeated at 80° C. for 4 hours and then cooled to room temperature. Thereaction was purified by silica gel chromatography eluting with 5-40%(10% NH₄OH/Methanol)/chloroform. The product fractions were collectedand concentrated in vacuo to yield(3R,4R)—N-(5-chloropyrazin-2-yl)-4′H-1-azaspiro[bicyclo[2.2.1]heptane-3,5′-oxazol]-2′-amineas a white wax (21 mg, 0.077 mmol, 33% yield). ¹H NMR (400 MHz,chloroform-d) δ ppm 9.39 (br. s., 1H) 8.45 (s, 1H) 6.32 (br. s., 1H)3.96 (s, 3H) 3.80-3.91 (m, 1H) 3.66 (d, J=9.54 Hz, 1H) 2.81-3.11 (m, 3H)2.66-2.81 (m, 2H) 2.48-2.66 (m, 2H) 2.22 (br. s., 1H) 1.47-1.63 (m, 1H).MS (LC/MS) R.T.=0.90; (M+H=276.13).

EXAMPLE 14(3R,4R)—N-(5-Chloropyrazin-2-yl)-4′H-1-azaspiro[bicyclo[2.2.1]heptane-3,5′-oxazol]-2′-amine

Step A: 2-Chloro-5-isothiocyanatopyrazine

A solution of 5-chloropyrazin-2-amine (12.95 g, 100 mmol) and1,1′-thiocarbonyldipyridin-2(1H)-one (27.9 g, 120 mmol) was stirred inDCM (200 mL) at room temperature for 1 h. The reaction was concentratedto ca. 100 mL volume and filtered through a pad of silica gel (1 L),washing with 10% EtOAc in hexanes. The filtrate was concentrated anddried to afford 2-chloro-5-isothiocyanatopyrazine (14.32 g, 83 mmol, 83%yield). ¹H NMR (400 MHz, chloroform-d) δ ppm 8.38 (d, J=1.26 Hz, 1H)8.18 (d, J=1.26 Hz, 1H). MS (LC/MS) R.T.=1.84; [M+H]⁺=172.09.

Step B:(3R,4R)—N-(5-Chloropyrazin-2-yl)-4′H-1-azaspiro[bicyclo[2.2.1]heptane-3,5′-oxazol]-2′-amine

2-Chloro-5-isothiocyanatopyrazine was reacted according to the method ofEXAMPLE 12, STEPS B&C to afford(3R,4R)—N-(5-chloropyrazin-2-yl)-4′H-1-azaspiro[bicyclo[2.2.1]heptane-3,5′-oxazol]-2′-amineas a light yellow wax (17 mg, 23% yield). ¹H NMR (400 MHz, DMSO-d₆) δppm 8.69-8.90 (m, 1H) 8.23-8.31 (m, 1H) 7.87-8.07 (m, 1H) 3.70-3.88 (m,1H) 3.51-3.69 (m, 1H) 2.72-2.96 (m, 2H) 2.55-2.70 (m, 4H) 2.30-2.43 (m,1H) 1.79-2.00 (m, 1H) 1.39-1.61 (m, 1H). MS(LC/MS) R.T.=0.97;(M+H=280.2).

EXAMPLE 15(3R,4R)—N-(4-Phenylpyrimidin-2-yl)-4′H-1-azaspiro[bicyclo[2.2.1]heptane-3,5′-oxazol]-2′-amine

Step A: 2-Isothiocyanato-4-phenylpyrimidine

4-Phenylpyrimidin-2-amine was reacted according to the method of EXAMPLE12 STEP A to afford 2-isothiocyanato-4-phenylpyrimidine. MS (LC/MS)R.T.=3.71; [M+H]⁺=214.09.

Step B:(3R,4R)—N-(4-Phenylpyrimidin-2-yl)-4′H-1-azaspiroibicyclo[2.2.1]heptane-3,5′-oxazol]-2′-amine

2-isothiocyanato-4-phenylpyrimidine was reacted according to the methodof EXAMPLE 13, STEPS B&C and the resultant product was further purifiedby preparative HPLC to yield(3R,4R)—N-(4-phenylpyrimidin-2-yl)-4′H-1-azaspiro[bicyclo[2.2.1]heptane-3,5′-oxazol]-2′-amine,TFA as a white wax (20.2 mg, 17% yield). ¹FINMR (400 MHz, MeOD) δ ppm8.78 (d, J=5.27 Hz, 1H) 8.15-8.31 (m, 2H) 7.89 (d, J=5.52 Hz, 1H)7.48-7.67 (m, 3H) 4.43 (d, J=11.04 Hz, 1H) 4.25 (d, J=11.29 Hz, 1H)3.90-4.06 (m, 1H) 3.76-3.89 (m, 1H) 3.41-3.67 (m, 5H) 2.43 (dd, J=5.14,1.88 Hz, 1H) 2.13-2.33 (m, 1H). MS(LC/MS) R.T.=1.35; (M+H=322.11).

EXAMPLES 16, 16a, 16b(3R*,4S*)-N-(Isoquinolin-3-yl)-4′H-1-azaspiroibicyclo[2.2.1]heptane-3,5′-oxazol]-2′-amine

Step A: (3S*,4S*)-3-(Aminomethyl)-1-azabicyclo[2.2.1]heptan-3-oldihydrochloride

((1R*,3S*,4S*)-3-(Aminomethyl)-3-hydroxy-1-ammoniobicyclo[2.2.1]heptan-1-yl)trihydroborate(2.6 g, 16.7 mmol) was reacted according to the method of EXAMPLE 4,STEP C to afford(3S*,4S*)-3-(aminomethyl)-1-azabicyclo[2.2.1]heptan-3-ol dihydrochlorideas a white solid (1.5 g, 42% yield). ¹H NMR (400 MHz, DMSO-d₆) δ ppm11.09 (br. s., 1H) 8.30 (br. s., 3H) 6.26 (br. s., 1H) 3.55 (d, J=8.53Hz, 1H) 3.00-3.38 (m, 7H) 2.86 (d, J=3.76 Hz, 1H) 1.86-2.07 (m, 1H) 1.77(d, J=5.77 Hz, 1H).

Step B:(3R*,4S*)-N-(Isoquinolin-3-yl)-4′H-1-azaspiro[bicyclo[2.2.1]heptane-3,5′-oxazol]-2′-amine

3-Isothiocyanatoisoquinoline and(3S*,4S*)-3-(aminomethyl)-1-azabicyclo[2.2.1]heptan-3-ol dihydrochloridewere reacted according to the method of EXAMPLE 6, STEP B to afford(3R*,4S*)-N-(isoquinolin-3-yl)-4′H-1-azaspiro[bicyclo[2.2.1]heptane-3,5′-oxazol]-2′-amine(80 mg, 0.27 mmol, 26% yield). ¹H NMR (400 MHz, DMSO-d₆) δ ppm 9.06 (s,1H) 8.00 (d, J=8.03 Hz, 1H) 7.78 (d, J=8.28 Hz, 1H) 7.62 (t, J=7.53 Hz,1H) 7.42 (t, J=7.40 Hz, 1H) 5.49 (br. s., 1H) 3.99 (br. s., 1H)3.53-3.86 (m, 2H) 2.92 (s, 1H) 2.59-2.84 (m, 4H) 2.34-2.49 (m, 2H) 1.60(t, J=11.67 Hz, 1H) 1.38 (d, J=12.55 Hz, 1H). MS(LC/MS) R.T.=0.70;(M+H=295.30).

This compound was further separated into enantiomers using a ChiralcelOD-H column, 30×250 mm, 5 um with a mobile phase of 20% MeOH with 0.1%DEA in carbon dioxide monitored at 250 nm. The separated peaks wereconcentrated in vacuo to yield white powders. The first peak off thecolumn yielded(3S,4R)—N-(isoquinolin-3-yl)-4′H-1-azaspiro[bicyclo[2.2.1]heptane-3,5′-oxazol]-2′-amine(EXAMPLE 16a 35.4 mg). ¹H NMR (400 MHz, chloroform-d) δ ppm 9.08 (br.s., 1H) 8.95 (s, 1H) 7.85 (d, J=8.28 Hz, 1H) 7.70 (d, J=8.78 Hz, 1H)7.51-7.60 (m, 1H) 7.32-7.42 (m, 2H) 4.07 (d, J=9.29 Hz, 1H) 3.70 (d,J=8.78 Hz, 1H) 3.33 (d, J=13.80 Hz, 1H) 3.17 (d, J=10.04 Hz, 1H)2.83-2.94 (m, 1H) 2.81 (d, J=4.52 Hz, 1H) 2.66 (dd, J=13.43, 2.64 Hz,1H) 2.44-2.56 (m, 2H) 1.71 (d, J=11.29 Hz, 1H) 1.37 (br. s., 1H).MS(LC/MS) R.T.=0.74;(M+H=295.27).

The second peak off the column yielded(3R,4S)—N-(isoquinolin-3-yl)-4′H-1-azaspiro[bicyclo[2.2.1]heptane-3,5′-oxazol]-2′-amine(EXAMPLE 16b, 44.2 mg). ¹H NMR (400 MHz, chloroform-d) δ ppm 9.08 (br.s., 1H) 8.95 (s, 1H) 7.85 (d, J=8.28 Hz, 1H) 7.70 (d, J=8.53 Hz, 1H)7.55 (t, J=7.65 Hz, 1H) 7.31-7.43 (m, 2H) 4.07 (d, J=9.03 Hz, 1H) 3.70(d, J=9.03 Hz, 1H) 3.28-3.38 (m, 1H) 3.17 (d, J=9.79 Hz, 1H) 2.77-2.95(m, 2H) 2.66 (dd, J=13.43, 2.64 Hz, 1H) 2.45-2.56 (m, 2H) 1.67-1.78 (m,1H) 1.38 (dd, J=13.55, 6.78 Hz, 1H). MS(LC/MS) R.T.=0.73; (M+H=295.57).

EXAMPLES 17, 17a, 17b(3R*,4S*)-N-(Thiazolo[5,4-b]pyridin-2-yl)-4′H-1-azaspiro[bicyclo[2.2.1]heptane-3,5′-oxazol]-2′-amine

Dimethyl thiazolo[5,4-b]pyridin-2-ylcarbonimidodithioate and(3S*,4S*)-3-(aminomethyl)-1-azabicyclo[2.2.1]heptan-3-ol dihydrochloridewere reacted according to the method of EXAMPLE 4, STEP D to afford(3R*,4S*)-N-(thiazolo[5,4-b]pyridin-2-yl)-4′H-1-azaspiro[bicyclo[2.2.1]heptane-3,5′-oxazol]-2′-amine(87.6 mg, 0.290 mmol, 67% yield). ¹H NMR (400 MHz, DMSO-d₆) δ ppm 9.16(br. s., 1H) 8.31 (dd, J=4.77, 1.51 Hz, 1H) 7.90 (dd, J=8.03, 1.51 Hz,1H) 7.38 (dd, J=8.03, 4.77 Hz, 1H) 4.03 (d, J=10.54 Hz, 1H) 3.81 (d,J=10.54 Hz, 1H) 2.96 (dd, J=13.55, 1.76 Hz, 1H) 2.73-2.88 (m, 3H)2.61-2.73 (m, 1H) 2.40-2.49 (m, 2H) 1.52-1.70 (m, 1H) 1.25-1.44 (m, 1H).MS(LC/MS) R.T.=0.32; (M+H=302.22).

This compound was further separated into individual enantiomers using aChiralcel OD-H column, 30×250 mm, Sum with a mobile phase of 20% MeOHwith 0.1% DEA in carbon dioxide monitored at 250 nm. The separated peakswere concentrated in vacuo to yield white powders. The first peak offthe column yielded(3S,4R)—N-(thiazolo[5,4-b]pyridin-2-yl)-4′H-1-azaspiro[bicyclo[2.2.1]heptane-3,5′-oxazol]-2′-amine(EXAMPLE 17a,18.2 mg). ¹H NMR (500 MHz, DMSO-d₆) δ ppm 8.89-9.39 (m, 1H)8.20-8.42 (m, 1H) 7.79-8.01 (m, 1H) 7.25-7.52 (m, 1H) 3.96-4.09 (m, 1H)3.72-3.87 (m, 1H) 2.94 (d, J=13.43 Hz, 1H) 2.71-2.86 (m, 3H) 2.60-2.71(m, 1H) 2.39-2.48 (m, 2H) 1.61 (dq, J=12.63, 5.35 Hz, 1H) 1.26-1.43 (m,1H). MS(LC/MS) R.T.=0.35; (M+H=301.91).

The second peak off the column yielded(3R,4S)—N-(thiazolo[5,4-b]pyridin-2-yl)-4′H-1-azaspiro[bicyclo[2.2.1]heptane-3,5′-oxazol]-2′-amine(EXAMPLE 17b 16.4 mg). ¹H NMR (400 MHz, DMSO-d₆) δ ppm 9.16 (br. s., 1H)8.31 (dd, J=4.64, 1.38 Hz, 1H) 7.90 (dd, J=8.03, 1.25 Hz, 1H) 7.38 (dd,J=8.28, 4.77 Hz, 1H) 4.03 (d, J=10.54 Hz, 1H) 3.81 (d, J=10.29 Hz, 1H)2.96 (dd, J=13.43, 1.38 Hz, 1H) 2.72-2.88 (m, 3H) 2.61-2.72 (m, 1H)2.33-2.48 (m, 2H) 1.53-1.76 (m, 1H) 1.27-1.50 (m, 1H). MS(LC/MS)R.T.=0.37; (M+H=301.95).

EXAMPLE 18(3R,4R)—N-(6-(Pyridin-4-yl)pyrimidin-4-yl)-4′H-1-azaspiro[bicyclo[2.2.1]heptane-3,5′-oxazol]-2′-amine

Dimethyl 6-(pyridine-4-yl)pyrimidin-4ylcarbonimidodithioate (38 mg, 0.14mmol) and (3S,4R)-3-(aminomethyl)-1-azabicyclo[2.2.1]heptan-3-ol, 2 HClwere reacted according to EXAMPLE 11 STEP E to give(3R,4R)—N-(6-(pyridine-4-yl)pyrimidin-4-yl)-4′H-1-azaspiro[bicycle[2.2.1]heptane-3,5′-oxazol]-2′-amine(24.1 mg, 54% yield) as a white waxy solid. 1H NMR (400 MHz, DMSO-d₆) δppm 9.33 (1H, br. S.), 8.87 (1H, s), 8.65-8.80 (2H, m), 8.07 (2H, br.S.), 7.36 (1H, s), 3.75-3.89 (1H, m), 3.66 (1H, d, J=10.04 Hz), 2.86(2H, d, J=14.56 Hz), 2.54-2.71 (4H, m), 2.30-2.43 (1H, m), 1.88 (1H, br.S.), 1.48 (1H, s). MS(LC/MS). R.T.=1.16 mins; (M+H=323.00).

EXAMPLE 19(3R,4R)—N-(6(1H-Imidazol-1-yl)pyrimidin-4-yl)-4′H-1-azaspiro[bicyclo[2.2.1]heptane-3,5′-oxazol]-2′-amine

Dimethyl 6-(1H-imidazol-1-yl)pyrimidin-4ylcarbonimidodithioate (119 mg,0.45 mmol) and (3S,4R)-3-(aminomethyl)-1-azabicyclo[2.2.1]heptan-3-ol, 2HCl were reacted in the same manner as EXAMPLE 11 STEP E to give(3R,4R)—N-(6-(1H-imidazol-1-yl)pyrimidin-4-yl)-4′H-1-azaspiro[bicycle[2.2.1]heptane-3,5′-oxazol]-2′-amine(24.2 mg, 17% yield) as a light yellow solid.

1H NMR (500 MHz, DMSO-d₆) δ ppm 9.27 (1H, br. s.), 8.65 (1H, s), 8.59(1H, s), 7.98(1H, br. s.), 7.11-7.20 (2H, m), 3.83 (1H, d, J=10.38 Hz),3.64 (1H, d, J=10.68 Hz), 2.72-2.89 (2H, m), 2.54-2.70 (4H, m),2.32-2.39 (1H, m), 1.86 (1H, br. s.), 1.42-1.58 (1H, m). MS(LC/MS).R.T.=1.10 mins; (M+H=311.96).

EXAMPLE 20(3R,4R)—N-(6-(4-Chloro-1H-imidazol-1-yl)pyrimidin-4-yl)-4′H-1-azaspiro[bicyclo[2.2.1]heptane-3,5′-oxazol]-2′-amine

Dimethyl 6-(4-chloro-1H-imidazol-1-yl)pyrimidin-4ylcarbonimidodithioate(65 mg, 0.217 mmol) and(3S,4R)-3-(aminomethyl)-1-azabicyclo[2.2.1]heptan-3-ol, 2 HCl werereacted according to EXAMPLE 11 STEP E to give(3R,4R)—N-(6-(4-chloro-1H-imidazol-1-yl)pyrimidin-4-yl)-4′H-1-azaspiro[bicycle[2.2.1]heptane-3,5′-oxazol]-2′-amine(37.6 mg, 50% yield) as a white solid.

1H NMR (500 MHz, DMSO-d₆) δ ppm 9.29 (1H, br. s.), 8.66 (1H, s), 8.58(1H, s), 8.12 (1H, s), 7.15 (1H, br. s.), 3.84 (1H, d, J=10.38 Hz), 3.65(1H, d, J=10.38 Hz), 2.73-2.95 (2H, m), 2.53-2.73 (4H, m), 2.37 (1H, dd,J=9.92, 3.51 Hz), 1.80-1.91 (1H, m), 1.36-1.55 (1H, m). MS(LC/MS).R.T.=1.35 mins; (M+H=346.20).

EXAMPLE 21(3R,4R)—N-(6-(1H-1,2,4-Triazol-1-yl)pyrimidin-4-yl)-4′H-1-azaspiro[bicyclo[2.2.1]heptane-3,5′-oxazol]-2′-amine

Dimethyl 6-(1H-1,2,4-triazol-1-yl)pyrimidin-4ylcarbonimidodithioate (62mg, 0.232 mmol) and(3S,4R)-3-(aminomethyl)-1-azabicyclo[2.2.1]heptan-3-ol, 2 HCl werereacted according to EXAMPLE 11 STEP E to give(3R,4R)—N-(6-(1H-1,2,4-triazol-1-yl)pyrimidin-4-yl)-4′H-1-azaspiro[bicycle[2.2.1]heptane-3,5′-oxazol]-2′-amine(38.2 mg, 52% yield) as a white solid.

1H NMR (400 MHz, CHLOROFORM-d) δ ppm 9.49 (1H, br. s.), 9.17 (1H, s),8.64 (1H, d, J=1.00 Hz), 8.11 (1H, s), 7.37-7.48 (1H, m), 3.92 (1H, d,J=9.54 Hz), 3.73 (1H, d, J=9.54 Hz), 2.87-3.05 (3H, m), 2.68-2.83 (2H,m), 2.52-2.71 (2H, m), 2.14-2.34 (1H, m), 1.47-1.77 (1H, m). MS(LC/MS).R.T.=1.22 mins; (M+H=313.2).

EXAMPLE 22(3R,4R)—N-(6-(4-Methyl-1H-imidazol-1-yl)pyrimidin-4-yl)-4′H-1-azaspiro[bicyclo[2.2.1]heptane-3,5′-oxazol]-2′-amine

Dimethyl 6-(4-methyl-1H-imidazol-1-yl)pyrimidin-4ylcarbonimidodithioate(62 mg, 0.232 mmol) and(3S,4R)-3-(aminomethyl)-1-azabicyclo[2.2.1]heptan-3-ol, 2 HCl werereacted according to EXAMPLE 11 STEP E to give(3R,4R)—N-(6-(4-methyl-1H-imidazol-1-yl)pyrimidin-4-yl)-4′H-1-azaspiro[bicycle[2.2.1]heptane-3,5′-oxazol]-2′-amine(30.2 mg, 20% yield) as a white powder.

1H NMR (400 MHz, DMSO-d₆) δ ppm 9.24 (1H, br. s.), 8.63 (1H, s), 8.46(1H, s), 7.66 (1H, s), 7.06 (1H, br. s.), 3.84 (1H, d, J=10.29 Hz), 3.65(1H, d, J=10.54 Hz), 2.73-2.98 (2H, m), 2.56-2.73 (4H, m), 2.31-2.46(1H,m), 2.18 (3H, s), 1.79-1.96 (1H, m), 1.36-1.57 (1H, m). MS(LC/MS).R.T.=0.40 mins; (M+H=326.2).

EXAMPLE 23(3R,4R)—N-(5-Methoxy-6-(pyrrolidin-1-yl)pyrimidin-4-yl)-4′H-1-azaspiro[bicyclo[2.2.1]heptane-3,5′-oxazol]-2′-amine

Step A: 5-Methoxy-6-(pyrrolidin-1-yl)pyrimidin-4-amine

In a flask was added 6-chloro-5-methoxypyrimidin-4-amine (500 mg, 3.13mmol) and pyrrolidine (0.523 ml, 6.27 mmol) in toluene (5 ml). Thereaction was heated to 80 C for 16 hours and then cooled to roomtemperature. The reaction was then concentrated to a white solid to give5-methoxy-6-(pyrrolidin-1-yl)pyrimidin-4-amine (514 mg, 84% yield).LC/MS R.T.=1.25 mins (M+H=195.2).

Step B: 4-Isothiocyanato-5-methoxy-6-(pyrrolidin-1-yl)pyrimidine

5-Methoxy-6-(pyrrolidin-1-yl)pyrimidin-4-amine was reacted according tothe method of EXAMPLE 6, STEP A to afford4-isothiocyanato-5-methoxy-6-(pyrrolidin-1-yl)pyrimidine, which wascarried on directly to the next step.

Step C:(3R,4R)—N-(5-Methoxy-6-(pyrrolidin-1-yl)pyrimidin-4-yl)-4′H-1-azaspiro[bicyclo[2.2.1]heptane-3,5′-oxazol]-2′-amine

4-Isothiocyanato-5-methoxy-6-(pyrrolidin-1-yl)pyrimidine and(3S,4R)-3-(aminomethyl)-1-azabicyclo[2.2.1]heptan-3-ol, 2 HCl werereacted according to the method of EXAMPLE 6, STEP B to afford(3R,4R)—N-(5-methoxy-6-(pyrrolidin-1-yl)pyrimidin-4-yl)-4′H-1-azaspiro[bicycle[2.2.1]heptane-3,5′-oxazol]-2′-amine(132 mg, 82% yield) as a white waxy solid.

1H NMR (400 MHz, DMSO-d₆) δ ppm 8.95 (1H, s), 7.97 (1H, s), 3.74 (1H, d,J=9.79 Hz), 3.62-3.65 (3H, m), 3.59 (4H, t, J=6.65 Hz), 3.54 (1H, d,J=10.04 Hz), 2.72-2.88 (2H, m), 2.55-2.68 (4H, m), 2.36 (1H, dd, J=9.91,3.64 Hz), 1.81-1.95 (5H, m), 1.39-1.55 (1H, m). MS(LC/MS). R.T.=2.54mins; (M+H=346.3).

EXAMPLE 24(3R,4R)—N-(Benzo[e][1,2,4]triazin-3-yl)-4′H-1-azaspiro[bicyclo[2.2.1]heptane-3,5′-oxazol]-2′-amine

Step A: Dimethyl benzo[e][1,2,4]triazin-3-ylcarbonimidodithioate

Benzo[e][1,2,4]triazin-3-amine was reacted according to the method ofEXAMPLE 3, STEP A to afford dimethylbenzo[e][1,2,4]triazin-3-ylcarbonimidodithioate. 1H NMR (400 MHz,CHLOROFORM-d) δ ppm 8.51 (1H, d, J=8.53 Hz), 7.96-8.01 (1H, m),7.89-7.96 (1H, m), 7.77 (1H, ddd, J=8.41, 6.78, 1.38 Hz), 2.69 (6H, s).

Step B:(3R,4R)—N-(Benzo[e][1,2,4]triazin-3-yl]-4′H-1-azaspiro[bicyclo[2.2.1]heptane-3,5′-oxazol]-2′-amine

Dimethyl benzo[e][1,2,4]triazin-3-ylcarbonimidodithioate (46.5 mg, 0.186mmol) and (3S,4R)-3-(aminomethyl)-1-azabicyclo[2.2.1]heptan-3-ol, 2 HClwere reacted according to EXAMPLE 11 STEP E to give(3R,4R)—N-(benzo[e][1,2,4]triazin-3-yl)-4′H-1-azaspiro[bicycle[2.2.1]heptane-3,5′-oxazol]-2′-amine(37 mg, 67% yield) as a rust colored powder.

1H NMR (400 MHz, DMSO-d₆) δ ppm 9.35 (1H, br. s.), 8.34 (1H, d, J=8.78Hz), 7.86-8.06 (2H, m), 7.68 (1H, ddd, J=8.28, 6.15, 2.13 Hz), 3.91 (1H,d, J=10.29 Hz), 3.72 (1H, d, J=10.29 Hz), 2.90 (1H, dd, J=13.55, 1.76Hz), 2.75-2.86 (1H, m), 2.67-2.75 (2H, m), 2.57-2.67 (2H, m), 2.39 (1H,dd, J=10.04, 3.76 Hz), 1.89-2.02 (1H, m), 1.51 (1H, tt, J=11.32, 4.61Hz). MS(LC/MS). R.T.=0.79 mins; (M+H=297.1).

EXAMPLE 25(3R,4R)—N-(5-Chlorobenzo[d]oxazol-2-yl)-4′H-1-azaspiro[bicyclo[2.2.1]heptane-3,5′-oxazol]-2′-amine

Dimethyl 5-chlorobenzo[d]oxazol-2-ylcarbonimidodithioate (51 mg, 0.186mmol) and (3S,4R)-3-(aminomethyl)-1-azabicyclo[2.2.1]heptan-3-ol, 2 HClwere reacted according to EXAMPLE 11, STEP E to give(3R,4R)—N-(5-chlorobenzo[d]oxazol-2-yl)-4′H-1-azaspiro[bicycle[2.2.1]heptane-3,5′-oxazol]-2′-amine(31 mg, 52% yield) as a light brown solid.

1H NMR (400 MHz, DMSO-d₆) δ ppm 9.11 (1H, br. s.), 7.37-7.57 (2H, m),7.19 (1H, dd, J=8.53, 2.01 Hz), 3.89 (1H, d, J=10.54 Hz), 3.70 (1H, d,J=10.54 Hz), 2.67-2.97 (4H, m), 2.57-2.67 (2H, m), 2.40 (1H, dd,J=10.29, 3.76 Hz), 1.79-1.96 (1H, m), 1.37-1.62 (1H, m). MS(LC/MS).R.T.=1.68 mins; (M+H=319.1).

EXAMPLE 26(3R,4R)—N-(Pyrrolo[1,2-f][1,2,4]triazin-4-yl)-4′H-1-azaspiro[bicyclo[2.2.1]heptane-3,5′-oxazol]-2′-amine

Step A: Dimethyl pyrrolo[1,2-f][1,2,4]triazin-4-ylcarbonimidodithioate

Pyrrolo[1,2-f][1,2,4]triazin-4-amine was reacted according to the methodof EXAMPLE 3, STEP A to afford dimethylpyrrolo[1,2-f][1,2,4]triazin-4-ylcarbonimidodithioate. MS(LC/MS).R.T.=3.198 mins; (M+H=239.1).

Step B:(3R,4R)—N-(Pyrrolo[1,2-f][1,2,4]triazin-4-yl)-4′H-1-azaspiro[bicyclo[2.2.1]heptane-3,5′-oxazo]-2′-amine

Dimethyl pyrrolo[1,2-f][1,2,4]triazin-4-ylcarbonimidodithioate (44 mg,0.186 mmol) and (3S,4R)-3-(aminomethyl)-1-azabicyclo[2.2.1]heptan-3-ol,2 HCl were reacted according to EXAMPLE 11, STEP E to give(3R,4R)—N-(pyrrolo[1,2-f][1,2,4]triazin-4-yl)-4′H-1-azaspiro[bicycle[2.2.1]heptane-3,5′-oxazol]-2′-amine(45mg, 82% yield) as a yellow wax.

1H NMR (400 MHz, DMSO-d₆) δ ppm 9.77 (1H, br. s.), 8.06 (1H, s),7.67-7.82 (1H, m), 6.61-6.88 (2H, m), 3.91 (1H, d, J=10.54 Hz), 3.72(1H, d, J=10.54 Hz), 2.89 (1H, dd, J=13.93, 2.38 Hz), 2.76-2.86 (1H, m),2.67-2.76 (2H, m), 2.58-2.67 (2H, m), 2.39 (1H, dd, J=10.29, 3.76 Hz),1.85-1.95 (1H, m), 1.45-1.57 (1H, m, J=11.36, 11.36, 4.77, 4.64 Hz).MS(LC/MS). R.T.=1.94 mins; (M+H=285.2).

EXAMPLE 27(3R,4R)—N-(Thieno[3,2-d]pyrimidin-4-yl)-4′H-1-azaspiro[bicyclo[2.2.1]heptane-3,5′-oxazol]-2′-amine

Step A: Dimethyl thieno[3,2-d]pyrimidin-4-ylcarbonimidodithioate

Thieno[3,2-d]pyrimidin-4- was reacted according to the method of EXAMPLE3, STEP A to afford Dimethylthieno[3,2-d]pyrimidin-4-ylcarbonimidodithioate, which was used directlyin the next step.

Step B:(3R,4R)—N-(Thieno[3,2-d]pyrimidin-4-yl)-4′H-1-azaspiro[bicyclo[2.2.1]heptane-3,5′-oxazol]-2′-amine

Dimethyl thieno[3,2,d]pyrimidin-4-ylcarbonimidodithioate(59 mg, 0.232mmol) and (3S,4R)-3-(aminomethyl)-1-azabicyclo[2.2.1]heptan-3-ol, 2 HClwere reacted according to EXAMPLE 11 STEP E to give(3R,4R)—N-(thieno[3,2,d]pyrimidin-4-yl)-4′H-1-azaspiro[bicycle[2.2.1]heptane-3,5′-oxazol]-2′-amine(55 mg, 75% yield) as a yellow wax.

1H NMR (400 MHz, DMSO-d₆) δ ppm 9.63 (1H, s), 8.71 (1H, s), 8.20 (1H, d,J=5.27 Hz), 7.47 (1H, d, J=5.52 Hz), 3.91 (1H, d, J=10.04 Hz), 3.72 (1H,d, J=10.29 Hz), 2.89 (1H, dd, J=13.30, 1.76 Hz), 2.75-2.86 (1H, m),2.67-2.75 (2H, m), 2.58-2.67 (2H, m), 2.40 (1H, dd, J=10.16, 3.89 Hz),1.86-1.97 (1H, m), 1.43-1.58 (1H, m). MS(LC/MS). R.T.=1.94 mins;(M+H=302.2).

EXAMPLE 28(3R,4R)—N-(7-Methylthieno[3,2-d]pyrimidin-4-yl)-4′H-1-azaspiro[bicyclo[2.2.1]heptane-3,5′-oxazol]-2′-amine

Step A: 7-Methylthieno[3,2-d]pyrimidin-4-amine

In a sealed tube was added 4-chloro-7-methylthieno[3,2-d]pyrimidine (2.0g, 10.83 mmol) and ammonium hydroxide (12.65 mmol, 325 mmol) in butanol(7 ml). The reaction was heated to 90 C for 4 hours and then cooled toroom temperature. The resulting white precipitate was collected to give7-methylthieno[3,2-d]pyrimidin-4-amine (1.4 g, 78% yield). 1H NMR (400MHz, DMSO-d₆) δ ppm 8.41 (1H, s), 7.74 (1H, s), 7.34 (2H, s), 2.34 (3H,d, J=1.00 Hz).

Step B: Dimethyl 7-methylthieno[3,2-d]pyrimidin-4-ylcarbonimidodithioate

7-Methylthieno[3,2-d]pyrimidin-4- was reacted according to the method ofEXAMPLE 3, STEP A to afford dimethyl7-methylthieno[3,2-d]pyrimidin-4-ylcarbonimidodithioate. MS(LC/MS).R.T.=3.44 mins; (M+H=270.1).

Step C:(3R,4R)—N-(7-Methylthieno[3,2-d]pyrimidin-4-yl)-4′H-1-azaspiro[bicyclo[2.2.1]heptane-3,5′-oxazol]-2′-amine

Dimethyl 7-methylthieno[3,2,d]pyrimidin-4-ylcarbonimidodithioate (63 mg,0.232 mmol) and (3S,4R)-3-(aminomethyl)-1-azabicyclo[2.2.1]heptan-3-ol,2 HCl were reacted according to EXAMPLE 11 STEP E to give(3R,4R)—N-(7-methylthieno[3,2,d]pyrimidin-4-yl)-4′H-1-azaspiro[bicycle[2.2.1]heptane-3,5′-oxazol]-2′-amine(38 mg, 49% yield) as a white waxy solid.

1H NMR (400 MHz, DMSO-d₆) δ ppm 9.63 (1H, s), 8.74 (1H, s), 7.83 (1H, d,J=1.00 Hz), 3.91 (1H, d, J=10.04 Hz), 3.68-3.77 (1H, m), 2.85-2.94 (1H,m), 2.76-2.85 (1H, m), 2.66-2.74 (2H, m), 2.58-2.66 (2H, m), 2.35-2.45(4H, m), 1.92 (1H, dd, J=11.04, 6.78 Hz), 1.41-1.59 (1H, m). MS(LC/MS).R.T.=2.07 mins; (M+H=316.2).

EXAMPLE 29(3R,4R)—N-(6-Methylbenzo[d]oxazol-2-yl)-4′H-1-azaspiro[bicyclo[2.2.1]heptane-3,5′-oxazol]-2′-amine

Dimethyl 6-methylbenzo[d]oxazol-2-ylcarbonimidodithioate (63 mg, 0.232mmol) and (3S,4R)-3-(aminomethyl)-1-azabicyclo[2.2.1]heptan-3-ol, 2 HClwere reacted according to EXAMPLE 11 STEP E to give(3R,4R)—N-(6-methylbenzo[d]oxazol-2-yl)-4′H-1-azaspiro[bicycle[2.2.1]heptane-3,5′-oxazol]-2′-amine(41 mg, 58% yield) as a white solid.

1H NMR (400 MHz, DMSO-d₆) δ ppm 9.04 (1H, s), 7.23-7.35 (2H, m),6.98-7.09 (1H, m), 3.87 (1H, d, J=10.29 Hz), 3.68 (1H, d, J=10.29 Hz),2.87 (1H, dd, J=13.55, 1.76 Hz), 2.74-2.84 (1H, m), 2.64-2.74 (2H, m),2.56-2.64 (2H, m), 2.32-2.43 (4H, m), 1.80-1.93 (1H, m), 1.42-1.56 (1H,m). MS(LC/MS). R.T.=2.22 mins; (M+H=299.1).

It will be evident to one skilled in the art that the present disclosureis not limited to the foregoing illustrative examples, and that it canbe embodied in other specific forms without departing from the essentialattributes thereof. It is therefore desired that the examples beconsidered in all respects as illustrative and not restrictive,reference being made to the appended claims, rather than to theforegoing examples, and all changes which come within the meaning andrange of equivalency of the claims are therefore intended to be embracedtherein.

1. A compound of formula I, or a stereoisomer thereof,

wherein R¹ is selected from the group consisting of isoxazolyl,pyrazolyl, oxazolyl, thiazolyl, imidazolyl, oxadiazolyl, thiadiazolyl,triazolyl, pyridinyl, pyrazinyl, pyridazinyl, pyrimidinyl, triazinyl,quinolinyl, isoquinolinyl, tetrahydroisoquinolinyl, quinoxalinyl,quinazolinyl, naphthyridinyl, indazolyl, indolyl, 2-indolonyl,benzisoxazolyl, benzoisothiazolyl, benzoxazolyl, benzothiazolyl,benzimidazolyl, furopyridinyl, thienopyridinyl, thienopyrimidinyl,isothiazolopyridinyl, thiazolopyridinyl, thiazolopyridinonyl,thiazolopyrazinyl, thiazolopyrimidinyl, triazolopyridinyl,triazolopyrazinyl, pyrrolotriazinyl, 5,6-dihydrobenzo[h]quinazolinyl,5H-chromeno[4,3-d]pyrimidinyl, 6,7-dihydro-5H-cyclopenta[d]pyrimidinyl,5,6,7,8-tetrahydroquinazolinyl, 7,8-dihydroquinazolin-5(6H)-onyl, andtetrahydrobenzothiazolyl, and is substituted with 0-3 substituentsindependently selected from the group consisting of C₁₋₄alkyl,C₃₋₇cycloalkyl, C₁₋₄haloalkyl, C₁₋₄alkoxy, C₁₋₄haloalkoxy,C₃₋₇cycloalkoxy, C₁₋₄alkylthio, phenoxy, benzyloxy, halo, hydroxy,cyano, nitro, C₁₋₄alkylsulfonyl, NR²R³, pyrrolidinonyl, methylenedioxy,furyl, thienyl, pyrazolyl, imidazolyl, thiazolyl, triazolyl, pyrazinyl,pyrimidinyl, naphthyl, C₁₋₄alkylamido, CONR²R³, pyridyl, phenyl, andbenzyl, and where imidazolyl, pyridyl, phenyl and benzyl are substitutedwith 0-2 substituents independently selected from the group consistingof halo, C₁₋₄alkyl, C₁₋₄alkoxy, C₁₋₄haloalkyl, C₁₋₄haloalkoxy, andNR²R³; R² is hydrogen, C₁₋₄alkyl, C₁₋₄hydroxyalkyl, or C₁₋₄aminoalkyl;R³ is hydrogen, C₁₋₄alkyl, C₁₋₄hydroxyalkyl, or C₁₋₄aminoalkyl; or R₂and R₃ taken together with the nitrogen atom to which they are attachedis azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl,N—(C₁₋₄alkyl)piperazinyl, morpholinyl, or homopiperidinyl; or apharmaceutically acceptable salt thereof.
 2. A compound of claim 1 whereR¹ is selected from the group consisting of dimethylisoxazolyl,(methyl)(phenyl)isoxazolyl, methylpyrazolyl, dimethylpyrazolyl,thienylpyrazolyl, methoxyphenylpyrazolyl, thiazolyl, bromothiazolyl,cyanothiazolyl, methylthiazolyl, dimethylthiazolyl,(methyl)(phenyl)thiazolyl, isopropylthiazolyl, butylthiazolyl,benzylthiazolyl, methoxyphenylmethylthiazolyl, phenylthiazolyl,chlorophenylthiazolyl, methoxyphenylthiazolyl,(methoxyphenyl)(methyl)thiazolyl, pyridinylthiazolyl,(phenyl)(methyl)imidazolyl, methyloxadiazolyl, ethyloxadiazolyl,methylthiadiazolyl, fluorophenylthiadiazolyl, furylthiadiazolyl,(dimethylcarboxamido)(methyl)thiazolyl, (pyrrolidinylCO)thiazolyl,phenyltriazolyl, pyridinyl, bromopyridinyl, chloropyridinyl,(chloro)(fluoro)pyridinyl, (chloro)(methyl)pyridinyl, dichloropyridinyl,fluoropyridinyl, cyanopyridinyl, (cyano)(methyl)pyridinyl,(cyano)(dimethyl)pyridinyl, methoxypyridinyl,(methylpyrrolidinyl)pyridinyl, phenylpyridinyl,methoxypyridinylpyridinyl, pyridazinyl, bromopyridazinyl,chloropyridazinyl, methylpyridazinyl, methoxypyridazinyl,methylthiopyridazinyl, pyrrolidinylpyridazinyl,pyrrolidinonylpyridazinyl, phenylpyridazinyl, pyridinylpyridazinyl,methoxypyridinylpyridazinyl, pyrimidinyl, (bromo)(isopropyl)pyrimidinyl,(bromo)(dimethyl)pyrimidinyl, (bromo)(cyclopropyl)pyrimidinyl,(bromo)(methoxy)pyrimidinyl, (bromo)(phenyl)pyrimidinyl,(bromo)(pyridinyl)pyrimidinyl, chloropyrimidinyl,(chloro)(dimethyl)pyrimidinyl, (methyl)(methoxy)pyrimidinyl,methylpyrimidinyl, ethylpyrimidinyl, (methyl)(phenyl)pyrimidinyl,dimethylpyrimidinyl, butylpyrimidinyl, isopropylpyrimidinyl,cyclopropylpyrimidinyl, methoxypyrimidinyl, dimethoxypyrimidinyl,isopropoxypyrimidinyl, cyclopentoxypyrimidinyl,difluoromethoxypyrimidinyl, trifluoroethoxypyrimidinyl,phenoxypyrimidinyl, methylthiopyrimidinyl, phenylpyrimidinyl,chlorophenylpyrimidinyl, methylphenylpyrimidinyl,methoxyphenylpyrimidinyl, (phenyl)(triazolyl)pyrimidinyl,pyridinylpyrimidinyl, methoxypyridinylpyrimidinyl,methoxypyrimidinylpyrimidinyl, naphthylpyrimidinyl, pyrazinyl,bromopyrazinyl, (bromo)(methoxy)pyrazinyl, chloropyrazinyl,methylpyrazinyl, dimethylpyrazinyl, butylpyrazinyl, cyanopyrazinyl,methoxypyrazinyl, isopropoxypyrazinyl, trifluoromethylpyrazinyl, andphenylpyrazinyl, and dimethyltriazinyl; or a pharmaceutically acceptablesalt thereof.
 3. A compound of claim 1 where R¹ is selected from thegroup consisting of dimethylpyridinoisoxazolyl, benzoxazolyl,chlorobenzoxazolyl, fluorophenylbenzoxazolyl, ethylphenylbenzoxazolyl,dimethylaminophenylbenzoxazolyl, pyridinylbenzoxazolyl, benzothiazolyl,acetamidobenzothiazolyl, bromobenzothiazolyl, chlorobenzothiazolyl,(chloro)(methyl)benzothiazolyl, (chloro)(methoxy)benzothiazolyl,fluorobenzothiazolyl, difluorobenzothiazolyl, cyanobenzothiazolyl,methylbenzothiazolyl, dimethylbenzothiazolyl,(methyl)(methoxy)benzothiazolyl, ethylbenzothiazolyl,trifluoromethylbenzothiazolyl, hydroxybenzothiazolyl,methoxybenzothiazolyl, ethoxybenzothiazolyl, isopropoxybenzothiazolyl,trifluoromethoxybenzothiazolyl, difluoromethoxybenzothiazolyl,dimethoxybenzothiazolyl, morpholinylbenzothiazolyl,(pyrrolidinylCO)benzothiazolyl, methylsulfonylbenzothiazolyl,thiazolopyridinyl, chlorothiazolopyridinyl, dimethylthiazolopyridinyl,benzyloxythiazolopyridinyl, difluoromethoxythiazolopyridinyl,benzotriazolyl, indolonyl, indazolyl, bromoindazolyl, chloroindazolyl,fluoroindazolyl, (methyl)(methoxy)indazolyl, methoxyindazolyl,trifluoromethylindazolyl, trifluoromethoxyindazolyl,difluoromethoxyindazolyl, benzimidazolyl, fluorobenzimidazolyl,methylbenzimidazolyl, (methyl)(methoxy)benzimidazolyl,methoxybenzimidazolyl, tetrahydrobenzothiazolyl, furopyridinyl,dimethylfuropyrimidinyl, thienopyrimidinyl, isopropylthienopyrimidinyl,dimethylthienopyrimidinyl, chlorotriazolopyridinyl,methyltriazolopyridinyl, trifluoromethyltriazolopyridinyl,methoxytriazolopyridinyl, triazolopyrazinyl, bromopyrrolotriazinyl,dimethylaminothiazolopyrimidinyl, thiazolopyazinyl,bromothiazolopyazinyl, methoxythiazolopyazinyl,methylthiothiazolopyazinyl, methoxythiazolopyrimidinyl,(methyl)(methoxy)thiazolopyrimidinyl, quinolinyl, bromoquinolinyl,fluoroquinolinyl, methylquinolinyl, (methyl)(methoxy)quinolinyl,isoquinolinyl, bromoisoquinolinyl, dichloroisoquinolinyl,methylisoquinolinyl, dimethylisoquinolinyl, quinoxalinyl,chloroquinoxalinyl, methylquinoxalinyl, methoxyquinoxalinyl,quinazolinyl, bromoquinazolinyl, naphthyridinyl,5,6-dihydrobenzo[h]quinazolinyl, 5H-chromeno[4,3-d]pyrimidinyl,6,7-dihydro-5H-cyclopenta[d]pyrimidinyl, 5,6,7,8-tetrahydroquinazolinyl,and 7,8-dihydroquinazolin-5(6H)-onyl; or a pharmaceutically acceptablesalt thereof.
 4. A compound of claim 1 where R¹ is selected from thegroup consisting of dichloropyridinyl, methoxypyridinyl,methoxypyrimidinyl, phenylpyrimidinyl, (methylphenyl)pyrimidinyl,pyridinylpyrimidinyl, chloropyrazinyl, benzothiazolyl,methoxybenzothiazolyl, thiazolopyridinyl, chlorothiazolopyridinyl,fluorothiazolopyridinyl, methoxythiazolopyridinyl, and isoquinoinyl; ora pharmaceutically acceptable salt thereof.
 5. A compound of claim 1where R¹ is selected from the group consisting of imidazolylpyrimidinyl,(chloroimidazolyl)pyrimidinyl, (triazolyl)pyrimidinyl,(methylimidazolyl)pyrimidinyl, (methoxy)(pyrrolidinyl)pyrimidinyl,benzo[e][1,2,4]triazinyl, chlorobenzoxazolyl,pyrrolo[1,2-f][1,2,4]triazinyl, thieno[3,2-d]pyrimidinyl,methylthieno[3,2-d]pyrimidinyl, and methylbenzoxazolyl; or apharmaceutically acceptable salt thereof.
 6. The stereoisomer of claim 1according to Formula Ic;

or a pharmaceutically acceptable salt thereof.
 7. The stereoisomer ofclaim 1 according to Formula Id;

or a pharmaceutically acceptable salt thereof.
 8. A compound of claim 6or 7 where R¹ is selected from the group consisting ofdichloropyridinyl, methoxypyridinyl, methoxypyrimidinyl,phenylpyrimidinyl, (methylphenyl)pyrimidinyl, pyridinylpyrimidinyl,chloropyrazinyl, benzothiazolyl, methoxybenzothiazolyl,thiazolopyridinyl, chlorothiazolopyridinyl, fluorothiazolopyridinyl,methoxythiazolopyridinyl, and isoquinoinyl; or a pharmaceuticallyacceptable salt thereof.
 9. A compound of claim 6 or 7 where R¹ isselected from the group consisting of imidazolylpyrimidinyl,(chloroimidazolyl)pyrimidinyl, (triazolyl)pyrimidinyl,(methylimidazolyl)pyrimidinyl, (methoxy)(pyrrolidinyl)pyrimidinyl,benzo[e][1,2,4]triazinyl, chlorobenzoxazolyl,pyrrolo[1,2-f][1,2,4]triazinyl, thieno[3,2-d]pyrimidinyl,methylthieno[3,2-d]pyrimidinyl, and methylbenzoxazolyl; or apharmaceutically acceptable salt thereof.
 10. A compound of claim 6 or 7where R¹ is selected from the group consisting of pyridinyl,pyrimidinyl, pyrazinyl, thiazolopyridinyl, isoquinolinyl, andbenzoxazolyl, and is substituted with 0-3 substituents independentlyselected from the group consisting of C₁₋₄alkyl, C₃₋₇cycloalkyl,C₁₋₄haloalkyl, C₁₋₄alkoxy, C₁₋₄haloalkoxy, C₃₋₇cycloalkoxy, halo,hydroxy, cyano, NR²R³, pyrrolidinonyl, methylenedioxy, furyl, thienyl,triazolyl, imidazolyl, thiazolyl, oxazolyl, pyrimidinyl, naphthyl,C₁₋₄alkylamido, CONR²R³, pyridyl, and phenyl, and where pyridyl, phenyl,thiazolyl and imidazolyl are substituted with 0-2 substituentsindependently selected from the group consisting of halo, C₁₋₄alkyl,C₁₋₄alkoxy, C₁₋₄haloalkyl, C₁₋₄haloalkoxy, and NR²R³; or apharmaceutically acceptable salt thereof.
 11. A compound of claim 1selected from the group consisting of(3R*,4S*)-N-(6-methoxybenzo[d]thiazol-2-yl)-4′H-1-azaspiro[bicyclo[2.2.1]heptane-3,5′-oxazol]-2′-amine,(3R*,4R*)-N-(6-methoxybenzo[d]thiazol-2-yl)-4′H-1-azaspiro[bicyclo[2.2.1]heptane-3,5′-oxazol]-2′-amine,(3R*,4R*)-N-(5-chlorothiazolo[5,4-b]pyridin-2-yl)-4′H-1-azaspiro[bicyclo[2.2.1]heptane-3,5′-oxazol]-2′-amine,(3R*,4R*)-N-(5-fluorothiazolo[5,4-b]pyridin-2-yl)-4′H-1-azaspiro[bicyclo[2.2.1]heptane-3,5′-oxazol]-2′-amine,(3R*,4R*)-N-(5-methoxythiazolo[5,4-b]pyridin-2-yl)-4′H-1-azaspiro[bicyclo[2.2.1]heptane-3,5′-oxazol]-2′-amine,(3R*,4R*)-N-(3,5-dichloropyridin-2-yl)-4′H-1-azaspiro[bicyclo[2.2.1]heptane-3,5′-oxazol]-2′-amine,(3R*,4R*)-N-(isoquinolin-3-yl)-4′H-1-azaspiro[bicyclo[2.2.1]heptane-3,5′-oxazol]-2′-amine,(3R,4R)—N-(isoquinolin-3-yl)-4′H-1-azaspiro[bicyclo[2.2.1]heptane-3,5′-oxazol]-2′-amine,(3S,4S)—N-(isoquinolin-3-yl)-4′H-1-azaspiro[bicyclo[2.2.1]heptane-3,5′-oxazol]-2′-amine,(3R*,4R*)-N-(thiazolo[5,4-b]pyridin-2-yl)-4′H-1-azaspiro[bicyclo[2.2.1]heptane-3,5′-oxazol]-2′-amineamine,(3S,4S)—N-(thiazolo[5,4-b]pyridin-2-yl)-4′H-1-azaspiro[bicyclo[2.2.1]heptane-3,5′-oxazol]-2′-amine,(3R,4R)-N-(thiazolo[5,4-b]pyridin-2-yl)-4′H-1-azaspiro[bicyclo[2.2.1]heptane-3,5′-oxazol]-2′-amine,(3R*,4R*)-N-(5-m-tolylpyrimidin-2-yl)-4′H-1-azaspiro[bicyclo[2.2.1]heptane-3,5′-oxazol]-2′-amine,(3R*,4R*)-N-(5-methoxypyridin-2-yl)-4′H-1-azaspiro[bicyclo[2.2.1]heptane-3,5′-oxazol]-2′-amine,(3R,4R)—N-(6-(pyridin-3-yl)pyrimidin-4-yl)-4′H-1-azaspiro[bicyclo[2.2.1]heptane-3,5′-oxazol]-2′-amine,(3R,4R)—N-(benzo[d]thiazol-2-yl)-4′H-1-azaspiro[bicyclo[2.2.1]heptane-3,5′-oxazol]-2′-amine,(3R,4R)—N-(6-methoxypyrimidin-4-yl)-4′H-1-azaspiro[bicyclo[2.2.1]heptane-3,5′-oxazol]-2′-amine,(3R,4R)—N-(5-chloropyrazin-2-yl)-4′H-1-azaspiro[bicyclo[2.2.1]heptane-3,5′-oxazol]-2′-amine,(3R,4R)—N-(4-phenylpyrimidin-2-yl)-4′H-1-azaspiro[bicyclo[2.2.1]heptane-3,5′-oxazol]-2′-amine,(3R*,4S*)-N-(isoquinolin-3-yl)-4′H-1-azaspiro[bicyclo[2.2.1]heptane-3,5′-oxazol]-2′-amine,(3S,4R)—N-(isoquinolin-3-yl)-4′H-1-azaspiro[bicyclo[2.2.1]heptane-3,5′-oxazol]-2′-amine,(3R,4S)—N-(isoquinolin-3-yl)-4′H-1-azaspiro[bicyclo[2.2.1]heptane-3,5′-oxazol]-2′-amine,afford(3R*,4S*)-N-(thiazolo[5,4-b]pyridin-2-yl)-4′H-1-azaspiro[bicyclo[2.2.1]heptane-3,5′-oxazol]-2′-amine,(3S,4R)—N-(thiazolo[5,4-b]pyridin-2-yl)-4′H-1-azaspiro[bicyclo[2.2.1]heptane-3,5′-oxazol]-2′-amine,and(3R,4S)—N-(thiazolo[5,4-b]pyridin-2-yl)-4′H-1-azaspiro[bicyclo[2.2.1]heptane-3,5′-oxazol]-2′-amine;or a pharmaceutically acceptable salt thereof.
 12. A compound of claim 1selected from the group consisting of(3R,4R)—N-(6-(pyridin-4-yl)pyrimidin-4-yl)-4′H-1-azaspiro[bicyclo[2.2.1]heptane-3,5′-oxazol]-2′-amine,(3R,4R)—N-(6-(1H-imidazol-1-yl)pyrimidin-4-yl)-4′H-1-azaspiro[bicyclo[2.2.1]heptane-3,5′-oxazol]-2′-amine,(3R,4R)—N-(6-(4-chloro-1H-imidazol-1-yl)pyrimidin-4-yl)-4′H-1-azaspiro[bicyclo[2.2.1]heptane-3,5′-oxazol]-2′-amine,(3R,4R)—N-(6-(1H-1,2,4-triazol-1-yl)pyrimidin-4-yl)-4′H-1-azaspiro[bicyclo[2.2.1]heptane-3,5′-oxazol]-2′-amine,(3R,4R)—N-(6-(4-methyl-1H-imidazol-1-yl)pyrimidin-4-yl)-4′H-1-azaspiro[bicyclo[2.2.1]heptane-3,5′-oxazol]-2′-amine,(3R,4R)—N-(5-methoxy-6-(pyrrolidin-1-yl)pyrimidin-4-yl)-4′H-1-azaspiro[bicyclo[2.2.1]heptane-3,5′-oxazol]-2′-amine,(3R,4R)—N-(benzo[e][1,2,4]triazin-3-yl)-4′H-1-azaspiro[bicyclo[2.2.1]heptane-3,5′-oxazol]-2′-amine,(3R,4R)—N-(5-chlorobenzo[d]oxazol-2-yl)-4′H-1-azaspiro[bicyclo[2.2.1]heptane-3,5′-oxazol]-2′-amine,(3R,4R)—N-(pyrrolo[1,2-f][1,2,4]triazin-4-yl)-4′H-1-azaspiro[bicyclo[2.2.1]heptane-3,5′-oxazol]-2′-amine,(3R,4R)—N-(thieno[3,2-d]pyrimidin-4-yl)-4′H-1-azaspiro[bicyclo[2.2.1]heptane-3,5′-oxazol]-2′-amine,(3R,4R)—N-(7-methylthieno[3,2-d]pyrimidin-4-yl)-4′H-1-azaspiro[bicyclo[2.2.1]heptane-3,5′-oxazol]-2′-amine,and(3R,4R)—N-(6-methylbenzo[d]oxazol-2-yl)-4′H-1-azaspiro[bicyclo[2.2.1]heptane-3,5′-oxazol]-2′-amine;or a pharmaceutically acceptable salt thereof.
 13. A pharmaceuticalcomposition comprising a therapeutically effective amount of a compoundof claim 1, or a pharmaceutically acceptable salt thereof, and apharmaceutically acceptable carrier.
 14. A method for the treatment ofschizophrenia, Alzheimer's Disease, cognitive disorders, rheumatoidarthritis, osteoarthritis, ulcerative colitis, Crohn's Disease, ordiabetes which comprises administering to a patient a therapeuticallyaffective amount of a compound of claim
 1. 15. The method of claim 14directed to schizophrenia.
 16. The method of claim 14 directed toAlzheimer's Disease.